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Heart-kidney listing is better than isolated heart listing for pediatric heart transplant candidates with significant renal insufficiency

Published:February 28, 2022DOI:https://doi.org/10.1016/j.jtcvs.2021.10.082

      Abstract

      Objectives

      Significant renal insufficiency is identified as a risk factor for post-transplantation mortality in pediatric heart transplant recipients. This study evaluates simultaneous heart-kidney transplantation listing outcomes compared with heart transplant for pediatric candidates with significant renal insufficiency.

      Methods

      The United Network for Organ Sharing registry was searched for patients (January 1987 to March 2020) who were simultaneously listed for a heart-kidney transplantation or for heart transplant with significant renal insufficiency at the time of listing. Significant renal insufficiency was defined as needing dialysis or having a low estimated glomerular filtration rate (<40 mL/min). Survival was calculated using Kaplan–Meier analysis.

      Results

      A total of 427 cases were identified; 109 were listed for heart-kidney transplantation, and 318 were listed for heart transplant alone. Median time on the waitlist was 101 days (interquartile range, 28-238) for heart-kidney transplantation listings compared with 39 days (14-86) and 23.5 days (6-51) for heart transplant recipients with a low estimated glomerular filtration rate (P = .002) or on dialysis (P < .001), respectively. Of all heart-kidney transplantation listings, 66% (n = 71) received a transplant compared with 54% (n = 173) of heart transplantation with significant renal insufficiency (P = .005) with a mean survival of 14.6 years (12.7-16.4 years) for heart transplant without significant renal insufficiency at transplantation and 7.6 years (5.4-9.9 years) for heart transplant with significant renal insufficiency at transplantation. At 1 year after listing, 69% of heart-kidney transplantation listed recipients were alive, compared with 51% of heart transplant listed recipients (P = .029). Heart-kidney transplantation recipients had better 1-year post-transplantation survival (86%) than heart transplantation with significant renal insufficiency at transplant (66%) (P = .001). There was no significant difference in the 1- and 5-year survivals of those undergoing heart transplantation listed with significant renal insufficiency but no significant renal insufficiency at the time of transplant (89% and 78%) and heart-kidney transplantation recipients (86% and 81%; P = .436).

      Conclusions

      Pediatric candidates with significant renal insufficiency listed for heart-kidney transplantation have superior waitlist and post-transplantation outcomes compared with those listed for heart transplant alone. Patients with significant renal insufficiency should be listed for heart-kidney transplantation, however; if their renal function improves significantly, heart transplant alone appears judicious.

      Graphical abstract

      Key Words

      Abbreviations and Acronyms:

      CI (confidence interval), ECMO (extracorporeal membrane oxygenation), eGFR (estimated glomerular filtration rate), HKTx (simultaneous heart-kidney transplant), HR (hazard ratio), HTx (heart transplant), IQR (interquartile range), IRB (Institutional Review Board), OPTN (Organ Procurement and Transplantation Network), SRI (significant renal insufficiency), UNOS (United Network for Organ Sharing), VAD (ventricular assist device)
      Figure thumbnail fx2
      Kaplan–Meier curves denoting post-transplant survival for HKTx, HTx with SRI at transplantation, and HTx without SRI at transplantation.
      Pediatric patients with heart failure with SRI have a better post-transplant survival with HKTx than with HTx alone. These patients also have a better survival from listing regardless of transplantation. However, if pediatric patients with heart failure with SRI at listing improve their renal function at the time of transplant, HTx alone is recommended.
      The current study analyzes waitlist and survival outcomes of children with SRI listed for HKTx compared with isolated HTx over the past 3 decades. SRI should be improved before transplantation with an isolated heart; otherwise, it is better to list for and offer a heart-kidney transplant.
      See Commentaries on pages 2032 and 2034.
      Heart transplantation (HTx) continues to be a successful management option for pediatric patients with end-stage heart failure. Survival in pediatric HTx has improved in recent decades due to advancements in management and organ allocation. The latest report by the Organ Procurement and Transplantation Network indicates a median survival of approximately 94% at 1 year and 85% at 5 years after transplantation.
      • Colvin M.
      • Smith J.M.
      • Hadley N.
      • Skeans M.A.
      • Uccellini K.
      • Goff R.
      • et al.
      OPTN/SRTR 2018 Annual data report: heart.
      Despite these positive outcomes, renal insufficiency often accompanies end-stage heart failure, complicating decisions regarding the course of treatment.
      • Grupper A.
      • Grupper A.
      • Daly R.C.
      • Pereira N.L.
      • Hathcock M.A.
      • Kremers W.K.
      • et al.
      Renal allograft outcome after simultaneous heart and kidney transplantation.
      Renal insufficiency poses a serious risk factor for waitlist and post-transplantation mortality, and several studies have demonstrated that renal dysfunction often progresses after HTx.
      • Grupper A.
      • Grupper A.
      • Daly R.C.
      • Pereira N.L.
      • Hathcock M.A.
      • Kremers W.K.
      • et al.
      Renal allograft outcome after simultaneous heart and kidney transplantation.
      • Ruderman I.
      • Sevastos J.
      • Anthony C.
      • Ruygrok P.
      • Chan W.
      • Javorsky G.
      • et al.
      Outcomes of simultaneous heart-kidney and lung-kidney transplantations: the Australian and New Zealand experience.
      • Schaffer J.M.
      • Chiu P.
      • Singh S.K.
      • Oyer P.E.
      • Reitz B.A.
      • Mallidi H.R.
      Heart and combined heart-kidney transplantation in patients with concomitant renal insufficiency and end-stage heart failure.
      Although currently uncommon in pediatrics, simultaneous heart-kidney transplantation (HKTx) may be a superior alternative for those with end-stage heart failure and renal insufficiency. Whereas HKTx may reduce the risk of post-transplantation renal failure and associated morbidity, a significantly longer waiting list time is a concern.
      • Grupper A.
      • Grupper A.
      • Daly R.C.
      • Pereira N.L.
      • Hathcock M.A.
      • Kremers W.K.
      • et al.
      Renal allograft outcome after simultaneous heart and kidney transplantation.
      ,
      • Schaffer J.M.
      • Chiu P.
      • Singh S.K.
      • Oyer P.E.
      • Reitz B.A.
      • Mallidi H.R.
      Heart and combined heart-kidney transplantation in patients with concomitant renal insufficiency and end-stage heart failure.
      With a limited donor pool and a growing waiting list for HTx, organs must be used as effectively as possible, but the lack of published data hinders optimal organ allocation.
      HKTx constitutes 81% of all multiorgan transplants in pediatric patients with cardiac disease; however, 82% of them are performed in North America, and few studies have analyzed the outcomes of this simultaneous approach.
      • Rossano J.W.
      • Cherikh W.S.
      • Chambers D.C.
      • Goldfarb S.
      • Hayes Jr., D.
      • Khush K.K.
      • et al.
      The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: twenty-first pediatric heart transplantation report-2018; focus theme: multiorgan transplantation.
       The results published have found HKTx to be a possible option for certain selected patients, especially in the adult population.
      • Grupper A.
      • Grupper A.
      • Daly R.C.
      • Pereira N.L.
      • Hathcock M.A.
      • Kremers W.K.
      • et al.
      Renal allograft outcome after simultaneous heart and kidney transplantation.
      • Ruderman I.
      • Sevastos J.
      • Anthony C.
      • Ruygrok P.
      • Chan W.
      • Javorsky G.
      • et al.
      Outcomes of simultaneous heart-kidney and lung-kidney transplantations: the Australian and New Zealand experience.
      • Schaffer J.M.
      • Chiu P.
      • Singh S.K.
      • Oyer P.E.
      • Reitz B.A.
      • Mallidi H.R.
      Heart and combined heart-kidney transplantation in patients with concomitant renal insufficiency and end-stage heart failure.
      • Rossano J.W.
      • Cherikh W.S.
      • Chambers D.C.
      • Goldfarb S.
      • Hayes Jr., D.
      • Khush K.K.
      • et al.
      The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: twenty-first pediatric heart transplantation report-2018; focus theme: multiorgan transplantation.
      • Weng P.L.
      • Alejos J.C.
      • Halnon N.
      • Zhang Q.
      • Reed E.F.
      • Tsai Chambers E.
      Long-term outcomes of simultaneous heart and kidney transplantation in pediatric recipients.
      Few studies examined the outcomes of dual-organ transplantation in pediatric patients. Approximately 62% of pediatric patients receiving an HKTx are on dialysis at the time of transplant.
      • Rossano J.W.
      • Cherikh W.S.
      • Chambers D.C.
      • Goldfarb S.
      • Hayes Jr., D.
      • Khush K.K.
      • et al.
      The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: twenty-first pediatric heart transplantation report-2018; focus theme: multiorgan transplantation.
      In all pediatric patients with cardiac disease, recipient dialysis has been associated with increased 1-year (hazard ratio [HR], 2.29) and 5-year (HR, 1.66) risk of mortality postoperatively.
      • Rossano J.W.
      • Cherikh W.S.
      • Chambers D.C.
      • Goldfarb S.
      • Hayes Jr., D.
      • Khush K.K.
      • et al.
      The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: twenty-first pediatric heart transplantation report-2018; focus theme: multiorgan transplantation.
      Thus, for patients on dialysis or at high risk for developing post-transplantation dialysis with end-stage heart failure, HKTx was found to be a superior alternative compared with isolated HTx in a national overview of adult patients and a center-specific study of pediatric candidates.
      • Schaffer J.M.
      • Chiu P.
      • Singh S.K.
      • Oyer P.E.
      • Reitz B.A.
      • Mallidi H.R.
      Heart and combined heart-kidney transplantation in patients with concomitant renal insufficiency and end-stage heart failure.
      ,
      • Weng P.L.
      • Alejos J.C.
      • Halnon N.
      • Zhang Q.
      • Reed E.F.
      • Tsai Chambers E.
      Long-term outcomes of simultaneous heart and kidney transplantation in pediatric recipients.
      Still, the lack of national overview with a pediatric population examining HKTx from listing limits the validity of these studies. Therefore, the purpose of this study is to analyze HKTx listing outcomes as opposed to isolated HTx listing for pediatric candidates with renal insufficiency to better recommend and evaluate treatment strategies for these patients.

      Materials and Methods

      This was a retrospective cohort study conducted using the Organ Procurement and Transplant Network and United Network for Organ sharing (UNOS) registry.
      The UNOS thoracic dataset was searched for pediatric patients (age <18 years) listed for HTx from January 1987 to March 2020. The pediatric HTx candidates were linked by direct identifiers (patient code, age, sex, listing date, and transplant date) to the renal transplant dataset to find patients simultaneously listed for a kidney transplant or those with significant renal insufficiency (SRI). SRI was defined as having a low estimated glomerular filtration rate (eGFR) that is less than 40 mL/min or being on dialysis. The final cohort was divided into 2 arms: (1) listings for HKTx that included patients listed for both a kidney and a heart transplant, and (2) listings for isolated HTx that included patients listed for a heart transplant only but had SRI at the time of listing. Patients on dialysis who also had low eGFR were included in the dialysis subgroup only. Patients listed for HTx with SRI who weighed less than 10 kg were excluded from the study because most centers do not perform transplants in those patients. All patients listed for HKTx were included in the study.

      Data Analysis

      Baseline characteristics of both cohort arms were obtained and presented as median (range/interquartile range [IQR]) and frequencies (percentages). Descriptive analysis was performed using chi-square for categorical data and nonparametric median tests for continuous data. Trends of listing and transplantation were examined over 5-year periods of time spanning from 1987 to 2020. Positive and negative waitlist outcomes were reported, and patients who reached any type of HTx were further analyzed. Patients who reached kidney transplantation alone without a heart transplant were excluded from further analysis. The Kaplan–Meier method with log-rank testing was used to compare the post-transplant survival of patients undergoing HKTx compared with those undergoing HTx alone. Patients who were listed for HTx with SRI were further divided into 2 subgroups: those who underwent transplantation with SRI and those who had a resolved SRI at the time of transplant (had an improved eGFR >40 mL/min at the time of transplant). Kaplan–Meier comparing the survival of the 2 HTx subgroups with HKTx at 1, 3, and 5 years post-transplantation was obtained. Survival analysis of patients listed for HKTx but receiving HTx alone was compared with those originally listed for HTx alone.
      Multivariate analyses were performed using Cox proportional hazards model using “a priori” technique, using recipient and donor variables all at once to identify independent predictors. The covariates included in the model were the risk factors included in Table 1 that showed significant difference between the HKTx and HTx with SRI listing (P < .001). Other variables added such as ventricular assist device (VAD) and donor-related variables were included based on previous literature considering these variables as predictors of survival. HRs were obtained. Data analysis was performed using SPSS software version 26 (IBM). The Institutional Review Board (IRB) of Cincinnati Children's Hospital Medical Center approved the study protocol and publication of data (IRB number: 2018-6837, IRB date of approval: 10/29/2018). Patient written consent for the publication of the study data was waived by the IRB because the analysis was done on a deidentified nationally available dataset.
      Table 1Characteristics of patients listed for simultaneous heart-kidney transplant and patients listed for heart transplant alone with significant renal insufficiency
      Listing characteristic
      Continuous variables are presented with median (IQR), and categorical variables are presented with percent (n).
      Type of listingP value
      HKTx (n = 109)HTx with SRI (n = 318)
      Age (y)13 (8.5-16)11 (5-15).035
       Infant (≤1 y)3% (3)5% (15).378
       2-11 y39% (42)48% (151).105
       >11 y59% (64)48% (152).49
      Male51% (56)59% (188).159
      Weight (kg)39 (22-56)37 (20-58).637
      eGFR (mL/min)37.88 (17.80-65.34)32.52 (24.73-39.27).584
      Dialysis40% (44)39% (124).800
      Diagnosis
       Cardiomyopathy43% (47)42% (133).813
       CHD17% (18)28% (90).015
       Retransplant37% (40)25% (78).014
       Other4% (4)5% (16)
      Inotrope use36% (39)63% (200)<.001
      VAD17% (18)19% (60).583
      Ventilator27% (23)48% (154)<.001
      ECMO11% (12)33% (105)<.001
      Bold P values represent significant variables.
      HKTx, Simultaneous heart-kidney transplant; HTx, heart transplant; SRI, significant renal insufficiency; eGFR, estimated glomerular filtration rate; CHD, congenital heart disease; VAD, ventricular assist device; ECMO, extracorporeal mechanical ventilation.
      Significant variables are represented with a boldface typed p value.
      Continuous variables are presented with median (IQR), and categorical variables are presented with percent (n).

      Results

      A total of 427 patients were identified. There were 109 patients (25.5%) listed for HKTx, of whom 39 (36%) were on dialysis and 50 (46%) had an eGFR less than 40 mL/min, whereas 318 (74.5%) were listed for HTx with SRI, of whom 124 (38.9%) were on dialysis and 194 (61.1%) had an eGFR less than 40 mL/min. Patient demographics are presented in Table 1. Patients listed for HKTx were older with a median age of 13 years (IQR, 8.5-16 years) compared with 11 years (IQR, 5-15 years) for patients listed for HTx (P = .035). HKTx listings were less likely to have a diagnosis of congenital heart disease (17% [n = 18] vs 28% [n = 90], P = .015) and more likely to be receiving a retransplant (37% [n = 40] vs 25% [n = 78], P = .014). Patients listed for HTx with SRI were more likely to be on inotropic support (63% [n = 200] vs 36% [n = 39]), ventilator support (48% [n = 154] vs 27% [n = 23]), and on extracorporeal membrane oxygenation (ECMO) (33% [n = 105] vs 11% [n = 12]) pretransplant (P < .001).
      Characteristics of patients listed for HTx alone who received HTx with SRI compared with those who received HTx with a resolved SRI at transplantation were obtained (Table 2). Patients who were listed for HTx alone who received a HTx with SRI were more likely to have hepatic dysfunction (defined as bilirubin >1.2) and to be on a ventilator at the time of transplant, and were less likely to have VAD at transplant compared with those who received transplantation with HTx with a resolved SRI at transplantation.
      Table 2Characteristics of patients listed for heart transplant alone who received a heart transplant with significant renal insufficiency compared with those who received a heart transplant without significant renal insufficiency


      Recipient characteristic
      Type of HTx (n = 171)P value
      HTx with SRI (n = 47)HTx without SRI (n = 124)
      Age (y), median (IQR)12 (8-15)12 (6-15).7
       Infant (0-1)1 (2.1%)4 (3.3%).7
       2-11 y21 (44.7%)59 (47.6%).7
       >11 y25 (53.2%)61 (49.1%).7
      Male, n (%)30 (63.8%)74 (59.7%).62
      Median weight (kg) (IQR)44 (28.7-54.8)40 (21.8-60.7).6
      Diagnosis, n (%)
       Cardiomyopathy19 (40.4%)67 (54%).34
       CHD12 (25.5%)30 (24.2%).34
       Retransplant14 (29.8%)24 (19.4%).34
       Other2 (4.3%)3 (2.4%).34
       Inotrope use, n (%)30 (63.8%)70 (56.5%).38
       Bilirubin >1.2, n (%)27 (57.4%)45 (36.2%).008
       VAD, n (%)11 (23.4%)51 (41.1%).031
       Ventilator, n (%)21 (44.7%)33 (26.6%).023
       ECMO, n (%)12 (25.5%)18 (14.5%).09
      Bold P values represent significant variables.
      HTx, Isolated heart transplantation; SRI, significant renal insufficiency; IQR, interquartile range; CHD, congenital heart disease; VAD, ventricular assist device; ECMO, extracorporeal mechanical ventilation; HKTx, simultaneous heart-kidney transplantation. Patients who were listed for HTx alone who received HTx with SRI were more likely to have hepatic dysfunction (defined as bilirubin >1.2) and to be on a ventilator at time of transplant, and were less likely to have VAD at transplant compared with those undergoing transplantation with HTx without SRI.
      Significant variables are represented with a boldface typed p value.

      Trends Over Time

      Patients with renal insufficiency represent 4.9% (427/8746) of all pediatric patients listed for a heart transplant from 1987 to 2020. The listing of patients with renal insufficiency, either as HKTx or HTx with SRI, has increased over time; 8 patients were listed before 1995 and increased to 113 patients in the time period between 2001 and 2005. After 2005, however, the absolute number of patients listed for HTx with renal insufficiency has declined (Table 3). Particularly, HKTx listing has been increasing steadily over time from 5 listings before 1995 up to 25 listings in the latest period (2016-2020). Listing of HTx with SRI has been decreasing during the past decade going from 92 (in 2011-2015) to 61 (in 2016-2020) patients (Table 3).
      Table 3Count of patients listed for simultaneous heart-kidney transplant, heart transplant with estimated glomerular filtration rate less than 40 mL/min, or heart transplant on dialysis at different time periods
      Listing periodType of listingTotal
      HKTxHTx with eGFR <40 mL/minHTx on dialysis
      <19955038
      1995-20009242255
      2001-2005206429113
      2006-201024502498
      2011-201526382892
      2016-202025181861
      Total109124194427
      HKTx, Simultaneous heart-kidney transplantation; HTx, isolated heart transplantation; eGFR, estimated glomerular filtration rate.

      Waitlist Outcomes

      Of those listed for HKTx, 51 of 109 (46.8%) underwent HKTx, 16 (14.7%) underwent HTx, and 4 of 109 (3.7%) received a kidney transplant alone. The other patients listed for HKTx did not receive a transplant (38/109; 34.8%), of whom 23 of 109 (21.1%) had negative outcomes (14/109 [12.8%] died on the waitlist and 9/109 [8.3%] were removed for a deteriorating condition; 13/109 [11.9%] had positive outcomes; 5/109 [4.6%] are alive but still waiting and 8/109 [7.3%] had an improved condition) (Figure 1, A). Among those with negative outcomes, 2 patients had a weight less than 10 kg at the time of listing. We speculate that the kidney transplant teams were probably waiting for them to have better weight at the time of transplant, but 1 of them died on the waitlist and the other was removed for worsening condition.
      Figure thumbnail gr1
      Figure 1A, Waitlist and 1- and 3-year post-transplantation outcomes for simultaneous/combined HKTx listings (n = 109) according to the transplant received: simultaneous HKTx, HTx alone, or kidney transplant alone. A total of 71 of 109 patients (65.1%) of HKTx listings reached transplantation. B, Waitlist and 1- and 3-year post-transplantation outcomes for HTx listings with SRI. A total of 173 of 318 (54%) reached transplantation. HKTx, Simultaneous heart-kidney transplant; Tx, transplantation; GFR, glomerular filtration rate.
      Of those listed for HTx with SRI, 173 of 318 (54.4%) received HTx and 145 of 318 (45.6%) did not receive a transplant, of whom 114 of 318 (35.8%) were removed from the waitlist due to adverse outcomes (91/318 [28.6%] died on the waitlist, and 23/318 [7.2%] were removed for a deteriorating condition; 24/318 [7.5%] had positive outcomes; 22/318 (6.9%) had an improved condition; and 2/318 (0.6%) are alive and still waiting) (Figure 1, B). Those listed for HTx with SRI had more than twice the waitlist mortality than those listed for HKTx (P = .001) (Table 4).
      Table 4Waitlist outcome comparison between heart-kidney transplant listings and heart transplant with significant renal insufficiency listings
      Outcome, % (n)Listing typeP value
      HKTx (n = 109)HTx with SRI (n = 318)
      HKTx46.8% (51)
      HTx alone14.7% (16)54.4% (173)<.001
      Kidney transplant alone3.7% (4)
      No transplant34.8% (38)45.6% (145).05
       Alive, still waiting4.6% (5/109)0.6% (2/318).005
       Died12.8% (14/109)28.6% (91/318).001
       Condition improved7.3% (8/109)6.9% (22/318).88
       Condition deteriorated8.3% (9/109)7.2% (23/318).73
       Other1.8% (2/109)2.2% (7/318).82
      Bold P values represent significant variables.
      HKTx, Simultaneous heart-kidney transplantation; HTx, isolated heart transplantation; SRI, significant renal insufficiency.
      Significant variables are represented with a boldface typed p value.

      Survival Analysis

      The median time on the waitlist was 101 days (IQR, 28-238 days) for HKTx listings compared with 39 days (IQR, 14-86 days) and 23.5 days (IQR, 6-51 days) for HTx patients with eGFR less than 40 mL/min (P = .002) or on dialysis (P < .001), respectively. Mean survival from listing of patients listed for HKTx was 11.3 years (95% confidence interval [CI], 8.7-13.9 years), patients listed for HTx with eGFR less than 40 mL/min was 7.7 years (6.5-9.1 years), and patients listed for HTx who are on dialysis was 7.6 years (5.7-9.6 years). Patients listed for HKTx had better overall survival from the time of listing compared with patients listed for HTx alone with eGFR less than 40 mL/min (P = .03) or on dialysis (P = .001) whether they underwent transplantation or not. There was no significant difference in survival for patients listed with HTx alone with low eGFR compared with those on dialysis (P = .18) (Figure 2).
      Figure thumbnail gr2
      Figure 2Kaplan–Meier curves showing survival analysis of patients listed for simultaneous HKTx, HTx with eGFR less than 40 mL/min, and HTx alone on dialysis, regardless of transplant. Log-rank testing showing that patients listed for HKTx had better survival than those listed for HTx with eGFR less than 40 mL/min (P = .03) or HTx on dialysis (P = .001). The 95% CI is represented by the shaded area. HKTx, Simultaneous heart-kidney transplant; eGFR, estimated glomerular filtration rate; HTx, heart transplant.

      Post-Transplantation Survival Analysis

      Among the total of 173 patients listed for HTx alone and having SRI (either low eGFR or on dialysis), 123 (71.1%) had improved eGFR (≥40 mL/min) at the time of transplant. Therefore, the cohort was divided into those who underwent HKTx, those who received HTx alone with SRI, and those who received HTx alone with improved renal function at the time of transplant. Two patients had no eGFR at time of transplant and were excluded from this analysis, so the total number of HTx included was 171 of 173. Patients with HKTx listing who received HKTx had better survival compared with patients listed for HTx alone receiving HTx with SRI at transplant (P = .001). However, HKTx recipients had similar survival compared with patients listed for isolated HTx who received HTx with improved renal function at transplant (P = .436) (Figures 3 and 4).
      Figure thumbnail gr3
      Figure 3Kaplan–Meier curves showing post-transplantation survival analysis at 1, 3, and 5 years of patients receiving simultaneous HKTx, HTx alone without SRI at transplantation who had SRI at listing and HTx alone with SRI at time of transplant. Log-rank testing showing that patients receiving HKTx had similar survival to those who received HTx without SRI (P = .436). The 95% CI is represented by the shaded area. HKTx, Simultaneous heart-kidney transplant; HTx, heart transplant; SRI, significant renal insufficiency; Tx, transplantation.
      Figure thumbnail gr7
      Figure 7A, Kaplan–Meier curves showing overall and the 1-, 3-, and 5-year post-transplantation survival of simultaneous HKTx listings receiving a transplant, regardless of transplant type received, stratified based on their post-transplantation dialysis status. There was no significant difference in the survival of the 2 groups using the log-rank test (P = .097). The 95% CI is represented by the shaded area. B, Kaplan–Meier curves showing overall and the 1-, 5-, and 10-year post-transplantation survival of HTx alone with SRI listings receiving a transplant, stratified based on their post-transplantation dialysis status. Log-rank testing shows that HTx with SRI listings who were not on dialysis postoperatively had significantly better 1-, 5-, and 10-year survival than those who were on dialysis (P < .001). The 95% CI is represented by the shaded area. HKTx, Simultaneous heart-kidney transplant; Tx, transplantation; HTx, heart transplant.
      Patients listed for and receiving HKTx had better survival compared with patients who were listed for HKTx but received HTx alone (P = .001) at 1, 3, and 5 years post-transplantation (Figure 5). There was no difference in survival between patients who were listed for HKTx but received an HTx alone and patients listed for and receiving HTx with SRI at transplant (P = .35) (Figure 6).
      Figure thumbnail gr4
      Figure 4Pediatric patients with heart failure with SRI should be listed for HKTx and receive an HKTx, unless these patients improve their renal function, then HTx alone is recommended. UNOS, United Network for Organ Sharing; HKTx, simultaneous heart-kidney transplant; HTx, heart transplant; SRI, significant renal insufficiency; eGFR, estimated glomerular filtration rate.

      Survival Trend Over Time

      There was no significant change in survival across eras for patients receiving HKTx or HTx alone with a resolved SRI. However, patients receiving HTx alone with SRI between 2010 and 2020 (n = 10) had better survival than those who underwent transplantation between 2000 and 2009 (n = 32) (P = .023).

      Cox Proportional Model

      Cox proportional hazard model shows that HKTx has a 2.6 times decreased mortality risk compared with HTx with SRI at the time of transplant (HR, 2.602; 95% CI, 1.327-5.102; P = .005) after adjusting for recipient and donor-related factors (Table 5).
      Table 5Cox proportional hazard model with recipient and donor-related risk factors
      VariablesHR95% CI for HRP value
      LowerUpper
      Recipient
       HKTxReference
       HTx without SRI at transplant1.0620.5532.04.856
       HTx with SRI at transplant2.6021.325.102.005
       Listing decades
      1987-1999Reference
      2000-20101.470.563.88.43
      2011-20201.320.443.95.621
       ECMO at transplant1.4590.7282.925.287
       IV inotropes at transplant0.8780.5281.460.61
       Ventilator at transplant0.9840.5281.460.959
       Any VAD at transplant0.7700.4101.445.416
       Diagnosis:
      CardiomyopathyReference
      CHD1.8870.9453.77.07
      Retransplant2.6971.5004.850<.001
      Other2.2960.6717.861.186
      Donor
       Age (y)1.0180.9931.04.16
       Donor cause of death: Stroke1.610.7543.43.20
       Ischemia time >4 h1.2140.7511.96.43
      Bold P values represent significant variables.
      HR, Hazard ratio; CI, confidence interval; HKTx, simultaneous heart-kidney transplantation; HTx, isolated heart transplantation; SRI, significant renal insufficiency; ECMO, extracorporeal mechanical ventilation; IV, intravenous; VAD, ventricular assist device; CHD, congenital heart disease. HKTx has a 2.6 times decreased mortality risk compared with HTx with SRI at time of transplantation (HR, 2.602; 95% CI, 1.327 -5.102; P = .005) after adjusting for recipient and donor-related factors (Table 5).
      Significant variables are represented with a boldface typed p value.
      Cox hazard model including an interaction between ECMO and transplant type (HTx alone or HKTx) was included and showed that ECMO had no significant effect on the difference in survival between HKTx and HTx alone with SRI (P = .5).

      Post-Transplantation Dialysis

      Of the 71 patients who were listed for HKTx and reached any type of transplant (HKTx, HTx, or kidney transplant), 28 (39.4%) were still on dialysis post-transplantation (Figure 1, A). Of the 173 patients who were listed for HTx with SRI and reached transplant, 44 (25.4%) were on dialysis postoperatively (Figure 1, B). Overall survivals of patients receiving dialysis post-transplantation versus those who did not, for HKTx and HTx with SRI listings, are presented in Figure 7, A and B, respectively. Patients listed for HKTx had similar survival whether they received post-transplant dialysis or not, regardless of the transplant type they received (P = .097) with a mean survival for patients on post-transplant dialysis being 7.9 years (95% CI, 5.2-10.7) and 13.9 years (95% CI, 10.3-17.5) for those not on post-transplant dialysis (Figure 7, A). Patients with SRI listed for and receiving HTx had significantly better overall survival when they did not undergo postoperative dialysis (P < .001) with a mean survival of 6.3 years (95% CI, 3.9-8.8) for HTx patients on post-transplant dialysis and 14.5 years (95% CI, 12.7-16.3) for HTx patients who are not on dialysis (Figure 7, B).
      Figure thumbnail gr5
      Figure 5Kaplan–Meier curves showing overall and the 1-, 3-, and 5-year post-transplantation survival of patients listed for and receiving a simultaneous HKTx compared with patients listed for HKTx but receiving an HTx alone. Log-rank testing shows that patients receiving an HKTx had a significantly better survival at 1, 3, and 5 years postoperatively than those receiving an HTx alone (P = .001). The 95% CI is represented by the shaded area. HKTx, Simultaneous heart-kidney transplant; Tx, transplantation; HTx, heart transplant.
      Figure thumbnail gr6
      Figure 6Kaplan–Meier curves showing survival of HTx alone with SRI patients and HTx alone patients who were initially listed as simultaneous HKTx. There was no significant difference in the survival of the 2 groups using log-rank test (P = .35). The 95% CI is represented by the shaded area. HTx, Heart transplant; HKTx, simultaneous heart-kidney transplant; SRI, significant renal insufficiency; Tx, transplantation.

      Discussion

      This large-scale analysis of the UNOS registry spanning more than 3 decades investigates outcomes of pediatric patients with cardiac and renal dysfunction being listed for or receiving HKTx compared with HTx alone. This study demonstrates that HKTx listing and transplant have been steadily increasing over time in the pediatric population. Between the years 2004 and 2018, there has been a 5-fold increase in the number of HKTx and 2.5 times increase in the percentage of HKTx among all heart transplant patients.
      • Shaw B.I.
      • Sudan D.L.
      • Boulware L.E.
      • McElroy L.M.
      Striking a balance in simultaneous heart kidney transplant: optimizing outcomes for all wait-listed patients.
      This increase not only reflects the improvements in the waitlist management and treatment of pediatric cardiac patients with renal insufficiency but also indicates the overall increased success of dual-organ transplantation.
      Patients listed for HKTx were found to have a statistically significant superior survival compared with those with SRI listed for isolated HTx, regardless of transplant. This suggests that the intent to treat patients as dual-organ recipients leads to better overall outcomes despite a longer waiting time. Currently, there is no consensus regarding the threshold of eGFR at which patients should be listed for HKTx in the pediatric population, and data on the adult population are also limited.
      • Weng P.L.
      • Alejos J.C.
      • Halnon N.
      • Zhang Q.
      • Reed E.F.
      • Tsai Chambers E.
      Long-term outcomes of simultaneous heart and kidney transplantation in pediatric recipients.
      In a study on isolated HTx in adults, eGFR less than 50 mL/min was significantly associated with increased 30-day mortality.
      • Weng P.L.
      • Alejos J.C.
      • Halnon N.
      • Zhang Q.
      • Reed E.F.
      • Tsai Chambers E.
      Long-term outcomes of simultaneous heart and kidney transplantation in pediatric recipients.
      ,
      • Ostermann M.E.
      • Rogers C.A.
      • Saeed I.
      • Nelson S.R.
      • Murday A.J.
      Steering group of the UK Cardiothoracic Transplant Audit. Pre-existing renal failure doubles 30-day mortality after heart transplantation.
       In pediatric HTx, Choudhry and colleagues
      • Choudhry S.
      • Wang Y.
      • Denfield S.W.
      • Cabrera A.G.
      • Price J.F.
      • Tunuguntla H.P.
      • et al.
      A recipient risk prediction tool for short-term mortality after pediatric heart transplantation.
      report eGFR less than 30 mL/min to be a risk factor for short-term mortality. Based on the literature, expert opinion, and center experience, a threshold of 40 mL/min for eGFR or being on dialysis was thought to be appropriate criteria to label pediatric patients with end-stage heart failure as having SRI requiring at least consideration for kidney transplant.
      Patients listed for HTx with renal insufficiency were found to be younger, to have congenital heart disease as diagnosis, and to be more ill, with approximately one-third of the cohort being on ECMO support, the majority of which could be from the previous decade, as ECMO support use has been decreasing over time.
      • Colvin M.
      • Smith J.M.
      • Hadley N.
      • Skeans M.A.
      • Uccellini K.
      • Goff R.
      • et al.
      OPTN/SRTR 2018 Annual data report: heart.
      In previous reports, it has been stated that the profile of patients with the highest 1-year mortality risk are those on cardiovascular support as well as undergoing dialysis for severe renal insufficiency.
      • Rossano J.W.
      • Cherikh W.S.
      • Chambers D.C.
      • Goldfarb S.
      • Hayes Jr., D.
      • Khush K.K.
      • et al.
      The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: twenty-first pediatric heart transplantation report-2018; focus theme: multiorgan transplantation.
      Therefore, it is not surprising that these patients have the worst outcomes and a high short-term mortality, even after adjusting for risk factors. Unfortunately, the current transplantation system focuses on prioritizing the sickest patients to get to transplant first, and this is reflected in the short waitlist time (<1 month) for HTx with SRI compared with a substantially longer time for HKTx patients. However, the postoperative outcomes of HTx patients with SRI were poor, and many of them died within the first year. This brings up the idea that perhaps our system should not focus on reaching transplant as an end goal but rather on ensuring the most years alive after transplantation for the whole community.
      Upon examination of the overall survival curve comparing the 3 listing groups (Figure 3), there are some clear messages: (1) If a patient with SRI at the time of transplant undergoes an HTx alone, their survival is poor with one-third dying in the first year and more than half of these patients dying within 5 years. (2) If you recover renal function by the time you undergo transplant, then isolated HTx is an acceptable strategy and HKTx does not provide a survival advantage. (3) There appears to be a significant difference in early hazard, but by 10 years and beyond, all 3 survival curves appear to be superimposed. Those who receive HTx alone who do not recover renal function have a high early mortality, but if they survive and recover renal function, they start to share the same late hazard as those who had HKTx or HTx alone but recovered renal function pretransplant. Hoskote and Burch
      • Hoskote A.
      • Burch M.
      Peri-operative kidney injury and long-term chronic kidney disease following orthotopic heart transplantation in children.
      report that during the first 10 years postoperatively, 3% to 10% of all heart transplant recipients develop chronic kidney dysfunction, with an increased risk in patients who already have perioperative worsening kidney function and hemodynamics. This leads us to say that if a pediatric heart transplant recipient has severe renal dysfunction, it is probably better to wait for their kidney function to recover instead of rushing to transplant or perform an HKTx. This is demonstrated in the current analysis in patients who have SRI at listing, but have improved renal function while awaiting transplant, have similar survival after isolated HTx relative to combined HKTx. This improvement in renal function can perhaps at times be accomplished with the use of VAD support. Hollander and colleagues
      • Hollander S.A.
      • Cantor R.S.
      • Sutherland S.M.
      • Koehl D.A.
      • Pruitt E.
      • McDonald N.
      • et al.
      Renal injury and recovery in pediatric patients after ventricular assist device implantation and cardiac transplant.
      showed that eGFR levels are significantly normalized 1 month after VAD implant, and that failure to go above the baseline value after implant leads to chronic kidney disease at 1 year postoperatively with an odds ratio of 12.5 for mortality. May and colleagues
      • May L.J.
      • Montez-Rath M.E.
      • Yeh J.
      • Axelrod D.M.
      • Chen S.
      • Maeda K.
      • et al.
      Impact of ventricular assist device placement on longitudinal renal function in children with end-stage heart failure.
      also report that children with preoperative acute kidney injury who receive a VAD implant start experiencing substantial renal function improvement from the first week postoperatively, lasting for months thereafter, suggesting that VAD support accelerates recovery and maintenance of normal kidney function.
      The overall trend in the last decade shows that patients receiving multiorgan transplants not only have favorable short- and long-term survival outcomes but also experience less acute and chronic rejection episodes.
      • Rossano J.W.
      • Cherikh W.S.
      • Chambers D.C.
      • Goldfarb S.
      • Hayes Jr., D.
      • Khush K.K.
      • et al.
      The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: twenty-first pediatric heart transplantation report-2018; focus theme: multiorgan transplantation.
      ,
      • Stehlik J.
      • Chambers D.C.
      • Zuckermann A.
      • Mehra M.R.
      • Khush K.K.
      Increasing complexity of thoracic transplantation and the rise of multiorgan transplantation around the world: insights from the International Society for Heart and Lung Transplantation Registry.
      In a single-center case-series study of 7 pediatric patients receiving HKTx, Weng and colleagues
      • Weng P.L.
      • Alejos J.C.
      • Halnon N.
      • Zhang Q.
      • Reed E.F.
      • Tsai Chambers E.
      Long-term outcomes of simultaneous heart and kidney transplantation in pediatric recipients.
      report consistent 1- and 5-year survivals of 86% in HKTx. This is comparable to the results reported in our study with an 86% at 1 year and 81% at 5 years postoperatively in a larger sample size. Chou and colleagues
      • Chou A.S.
      • Habertheuer A.
      • Chin A.L.
      • Sultan I.
      • Vallabhajosyula P.
      Heart-kidney and heart-liver transplantation provide immunoprotection to the cardiac allograft.
      report in their UNOS analysis a significantly better rate of treatment for acute rejection within the first year postoperatively in HKTx and heart-liver combined transplantation. In that study, the authors also report significant improvement in cardiac allograft survival in HKTx compared with heart alone transplants with an odds ratio of 0.58.
      • Chou A.S.
      • Habertheuer A.
      • Chin A.L.
      • Sultan I.
      • Vallabhajosyula P.
      Heart-kidney and heart-liver transplantation provide immunoprotection to the cardiac allograft.
      Thus, multiorgan transplants, including HKTx, provide protection from immune-related morbidity.
      To date, this is the largest comparison of HKTx versus isolated HTx performed in the pediatric population with SRI. The study combines data from 2 large UNOS registries (Thoracic and Renal), spanning 3 decades, and provides an analysis considering preoperative, perioperative, and postoperative characteristics. The study differentiates between patients with improved renal function and those with severe insufficiency at the time of transplant, stressing the importance of improving renal function before reaching transplantation for better postoperative outcomes. The study also includes an analysis of the “intention-to-treat” with HKTx versus HTx, which might allow physicians to make well-informed decisions from the time of listing.

      Study Limitations

      The limitations of the study are associated with the dataset chosen and the restriction imposed by the availability of variables in both UNOS registries. Information on center performance with the lack of a consensus on threshold to determine HKTx listing is not available; therefore, this complexity was not considered. The sample size is also a limitation, although the number of HKTxs is the highest among multiorgan transplants; however, the absolute numbers are still low. Future studies that include a bigger sample or that use predictive models to estimate survival of HKTx are needed.

      Conclusions

      Pediatric patients with heart failure with SRI should be considered for HKTx. Despite longer waitlist times, patients with SRI listed for HKTx have a better overall survival than those patients listed for isolated HTx, regardless of transplant. Patients with SRI have a better post-transplant survival with HKTx than with HTx alone. However, if these patients improve their renal function then HTx alone is recommended (Figure 4). Because post-transplant outcomes are poor, it might not be prudent for pediatric cardiac patients with SRI (low eGFR or on dialysis) to undergo heart transplant alone.

      Conflict of Interest Statement

      C.C. is a consultant for Azurity Pharmaceuticals. All other authors reported no conflicts of interest.
      The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
      This work is supported by the National Heart, Lung, and Blood Institute ( 1R01HL147957 ). Additionally, this work was supported in part (UNOS STAR dataset) by Health Resources and Services Administration contract 234-2005-37011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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      Linked Article

      • Commentary: Heart transplantation listing for children with significant renal insufficiency: The need for a paradigm shift
        The Journal of Thoracic and Cardiovascular SurgeryVol. 164Issue 6
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          Dani and colleagues1 from Cincinnati review the Organ Procurement and Transplantation Network/United Network for Organ Sharing Registry with focus on pediatric patients (younger than age 18 years) with significant renal insufficiency (defined as having a estimated glomerular filtration rate <40 mL/min/1.73 m2 and/or being on dialysis) at time of listing for heart transplantation (HTx) (n = 318) or combined heart–kidney transplantation (HKTx) (n = 109). They found that those listed for HKTx were more likely to undergo transplantation than those listed for HTx (66% vs 54%; P = .005) and more likely to be alive at 1 year after listing (69% vs 51%; P = .029).
        • Full-Text
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      • Commentary: Kidney at the heart of the matter
        The Journal of Thoracic and Cardiovascular SurgeryVol. 164Issue 6
        • Preview
          Significant renal insufficiency (SRI) in pediatric patients with progressive heart failure is common, and may affect transplant candidacy and potentially compromise early and late outcomes after heart transplant. Simultaneous heart–kidney transplant (HKTx) has been shown to be an effective treatment strategy for selected patients with end-stage heart failure and SRI, but it has rarely been done in pediatric populations.1,2 Dani and colleagues3 conducted a large-scale study using United Network for Organ Sharing Registry data spanning more than 3 decades to determine whether or not listing for HKTx is superior to listing for heart transplantation (HTx) alone in patients with SRI.
        • Full-Text
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