Visual Abstract
Keywords: kidney transplantation, organ transplant, renal failure, renal transplantation, transplant outcomes
Abstract
Key Points
Simultaneous heart–kidney transplant is associated with high rates of kidney graft failure which are worse when compared with kidney transplant alone.
The major causes of kidney graft failure in simultaneous heart–kidney transplant recipients were patient death and primary nonfunction of kidney graft.
Background
The indications and outcomes of simultaneous heart–kidney transplantation (SHKT) remain suboptimally defined. Risk factors for renal graft failure after SHKT also remain poorly defined.
Methods
We analyzed the renal graft outcomes among SHKT recipients using United Network for Organ Sharing database from 2015 to 2020. To evaluate for factors associated with poor renal outcomes, we compared SHKT and kidney transplantation alone recipients using propensity score matching.
Results
Among SHKT recipients, the rate of primary nonfunction (PNF) of kidney graft was 3%, the 30-day kidney graft failure rate was 7.0%, and the 30-day post-transplant mortality rate was 4.1%. The incidence of kidney delayed graft function was 27.5%. Kidney graft failure was seen early post-SHKT with most common causes of patient death (43.9%) and PNF of kidney graft (41.5%). One- and 2-year patient survival was 89.2% and 86.5%, and 1- and 2-year freedom from kidney graft failure was 85.4% and 82.7%, respectively. In subgroup analysis of SHKT recipients, use of pretransplant mechanical cardiac support (adjusted odds ratio [aOR], 2.57; P = 0.017), higher calculated panel reactive antibody (aOR, 1.76; P = 0.016), and older donor age per 10 years (aOR, 1.94; P = 0.001) were associated with PNF. Pretransplant extracorporeal membrane oxygenation support was associated with the increased risk of 30-day recipient mortality (aOR, 5.55; P = 0.002). Increased 30-day graft failure was seen in SHKT recipients with pretransplant mechanical cardiac support (aOR, 1.77; P = 0.038) and dialysis at the time of transplant (aOR, 1.72; P = 0.044). Multivariable Cox hazard analysis demonstrated that SHKT, when compared with kidney transplantation alone, is associated with increased kidney graft failure (hazard ratio, 2.56; P < 0.001) and recipient mortality (hazard ratio, 2.65; P < 0.001).
Conclusions
SHKT is associated with high rates of kidney graft failure. Identification of risk factors of renal graft failure can help optimize recipient selection for SHKT versus kidney after heart transplantation, especially after introduction of the new safety-net policy.
Introduction
Kidney dysfunction is a common sequela of end-stage heart disease and is associated with worse overall and graft survival (GS) after heart transplantation (HT).1–5 The prevalence of kidney dysfunction in HT candidates with advanced heart failure has increased over the past decade from 3.9% in 2009 to 7.5% 2019,6 leading to increase in the number of SHKT performed in the United States.6–10
Although simultaneous heart–kidney transplantation (SHKT) was shown to improve survival in HT recipients with end-stage renal dysfunction,9 it is unclear whether similar benefit extends to HT recipients with mild-to-moderate kidney dysfunction.9–12 SHKT is often more complex than HT or kidney transplantation alone (KTA) because of the combination of medical and surgical challenges.13,14 Owing to other perioperative risk factors, such as prolonged hemodynamic instability, worse kidney transplant outcomes, such as kidney delayed graft function (KDGF), primary allograft dysfunction, or graft loss, maybe higher in SHKT recipients compared with KTA.14,15 During the period 2002–2010, Choudhury et al. showed that kidney GS is comparable between SHKT and KTA.7 Since then, the characteristics of SHKT recipients have changed with patients being older and with more medical comorbidities, along with the significant hemodynamic challenges introduced by the new heart allocation policy.8
To help address these questions, we conducted the analysis of the United Network for Organ Sharing (UNOS) database focusing on the kidney allograft outcomes of SHKT and then compared them with outcomes of KTA.
Methods
Data Source and Study Group
The adult kidney transplant recipients aged 18 years or older between January 2015 and December 2020 were retrospectively analyzed using the deidentified UNOS database. The patients were categorized into groups: SHKT (N=1122) and KTA (N=52,296). Recipients with retransplants, other multiorgan transplants, living donations, and donations from cardiac death were excluded. This study was considered exempt by the Institutional Review Board because of secondary data usage.
Outcomes and Definitions
The primary end point was kidney graft failure (Supplemental Material), and secondary endpoints were mortality, KDGF,16 primary nonfunction (PNF), and kidney allograft rejection episodes in the initial admission, 6 months, and 1 year. eGFR was calculated with the CKD Epidemiology Collaboration equation.17 The causes of mortality and kidney graft failure were also reviewed. To analyze the risk factors of kidney graft failure, KDGF, and PNF among SHKT recipients, a subgroup analysis was performed by combining the thoracic data file.
Statistics
Nonparametric analysis was used to compare continuous variables between groups (Mann–Whitney U test), and the chi-square test or Fisher's exact test was used for categorical data. The propensity score matching was performed using recipient and donor variables as detailed in the Supplemental Material.
The overall survival (OS) and GS were calculated from the date of transplant to the date of event using the Kaplan–Meier method. The log-rank test was used to compare survival curves. To eliminate the effect of early mortality, additional survival analysis was performed after excluding patients who had kidney graft failure within 30, 60, and 90 days. Logistic regression analysis was applied to assess the association of multiple covariates with events of KDGF. Cox proportional hazard regression analysis was applied to identify the factors which were associated with OS and GS during the entire follow-up period. As subgroup analysis in SHKT, logistic regression analysis was applied to assess the association of multiple covariates with events of PNF, 30-day mortality, and 30-day kidney graft failure.
The results were presented as odds ratios and hazard ratios and reported with 95% confidence intervals (CIs). All variables with a value of P < 0.2 in the univariable model were entered into the multivariable model. The stepwise backward model selection method was used to build the most parsimonious multivariable model. Adjusted odds ratio (aOR) and adjusted hazard ratio (aHR) were shown in the multivariable models. For all statistical analyses, P < 0.05 was considered as statistically significant. All statistical analyses were performed using R-Studio using R version 4.1.1 (R Studio, Boston, MA).
Results
Simultaneous Heart–Kidney Transplantation
The SHKTs performed in the United States increased significantly during the study period (Figure 1A), with highest percentage of SHKT performed in region 7 (3.6%) and the highest number of SHKT performed in region 5 (n=299) (Figure1B).
Figure 1.
Annual trends of simultaneous heart–kidney transplantation and KTA and UNOS regional distribution of simultaneous heart–kidney transplantation. (A) Trends of number of simultaneous heart–kidney transplantation and KTA. (B) Number and percentage of heart and kidney transplantation in various UNOS regions. KTA, kidney transplantation alone; UNOS, United Network for Organ Sharing.
Among SHKT recipients, the 30-day post-transplant mortality rate was 4.1% and 30-day kidney graft failure rate was 7.0%. PNF of kidney graft was seen in 3% of SHKT recipients. The incidence of delayed graft function of kidney (KDGF) was 27.5%. Common causes of kidney graft failure in this cohort were patient death (43.9%) and PNF of kidney graft (41.5%). Most common causes of 30-day mortality in this cohort were multisystem organ failure (28%) and infection/sepsis (22%).
One-year and 2-year patient survival was 89.2% and 86.5%, and 1-year and 2-year freedom from kidney graft failure was 85.4% and 82.7%, respectively.
Comparison of Simultaneous Heart–Kidney Transplantation and KTA
Recipient Characteristics
In the nonmatched cohort, SHKT recipients were older (median: 57 versus 55 years, P < 0.001), more male (78.3% versus 59.7%, P < 0.001), and White (49.2% versus 34.0%, P < 0.001) (Table 1). SHKT recipients had higher incidence of diabetes (45.6% versus 38%, P < 0.001) and peripheral vascular disease (13% versus 11%, P = 0.071), with lower body mass index (27.1 versus 28.2 kg/m2, P < 0.001). SHKT recipients had lower pretransplant serum creatinine level (2.6 versus 8.0 mg/dl, P < 0.001) and a lower rate of dialysis at the time of transplant (30% versus 91%, P < 0.001). The waiting time was significantly shorter in SHKT (123 versus 1680 days, P < 0.001). In the matched cohort, pretransplant characteristics were balanced except for serum creatinine (SHKT: 2.7 mg/dl versus KTA: 6.2 mg/dl, P < 0.001) (Supplemental Table 1).
Table 1.
Characteristics of patients with simultaneous heart–kidney transplantation and kidney transplantation alone
| Variable | SHKT | KTA | P Value |
|---|---|---|---|
| n=1122 | n=52,296 | ||
| Recipient characteristics | |||
| Age, yr, median (IQR) | 57.0 (49.0–63.0) | 55.0 (44.0–64.0) | <0.001 |
| Sex, No. (%) | <0.001 | ||
| Female | 244 (22) | 21,063 (40) | |
| Male | 878 (78) | 31,233 (60) | |
| Race, No. (%) | <0.001 | ||
| White | 549 (49) | 17,786 (34) | |
| Black | 379 (34) | 18,889 (36) | |
| Hispanic | 110 (9.8) | 10,330 (20) | |
| Asian | 59 (5.3) | 4031 (7.7) | |
| Others | 25 (2.2) | 1260 (2.4) | |
| Blood type, No. (%) | 0.003 | ||
| A | 403 (36) | 18,233 (35) | |
| AB | 64 (5.7) | 2813 (5.4) | |
| B | 199 (18) | 7553 (14) | |
| O | 456 (41) | 23,697 (45) | |
| BMI, kg/m2, median (IQR) | 27.1 (23.6–30.5) | 28.2 (24.5–32.3) | <0.001 |
| Peripheral vascular disease, No. (%) | 136 (13) | 5621 (11) | 0.071 |
| Dialysis, No. (%) | 337 (30) | 47,308 (90) | <0.001 |
| HCV serostatus, No. (%) | 31 (2.8) | 2841 (5.5) | <0.001 |
| Diabetes, No. (%) | 511 (46) | 19,670 (38) | <0.001 |
| List of waiting days, median (IQR) | 49.5 (13–171) | 634 (164–1409) | <0.001 |
| Serum creatinine, mg/dl, median (IQR) | 2.6 (2.0–3.8) | 8.0 (5.9–10.6) | <0.001 |
| Serum albumin, mg/dl, median (IQR) | 3.70 (3.30–4.10) | 4.00 (3.70–4.40) | <0.001 |
| cPRA, No. (%) | <0.001 | ||
| <25% | 989 (88) | 38,848 (74) | |
| 25%–50% | 56 (5.0) | 3810 (7.3) | |
| 50%–75% | 45 (4.0) | 3205 (6.1) | |
| >75% | 32 (2.9) | 6433 (12) | |
| No. of HLA mismatch, No. (%) | <0.001 | ||
| 0 | 0 (0) | 2128 (4.1) | |
| 1 | 5 (0.5) | 488 (0.9) | |
| 2 | 27 (2.4) | 2111 (4.0) | |
| 3 | 127 (12) | 6960 (13) | |
| 4 | 268 (24) | 14,510 (28) | |
| 5 | 420 (38) | 17,649 (34) | |
| 6 | 257 (23) | 8450 (16) | |
| Donor characteristics | |||
| Age, yr, median (IQR) | 30.0 (24.0–39.0) | 39.0 (27.0–51.0) | <0.001 |
| Sex, No. (%) | <0.001 | ||
| Female | 294 (26) | 20,987 (40) | |
| Male | 828 (74) | 31,309 (60) | |
| Race, No. (%) | <0.001 | ||
| White | 688 (61) | 33,756 (65) | |
| Black | 146 (13) | 8012 (15) | |
| Hispanic | 242 (22) | 8077 (15) | |
| Asian | 27 (2.4) | 1356 (2.6) | |
| Others | 19 (1.7) | 1095 (2.1) | |
| Blood type, No. (%) | <0.001 | ||
| A | 361 (32) | 19,426 (37) | |
| AB | 25 (2.2) | 2017 (3.9) | |
| B | 125 (11) | 6331 (12) | |
| O | 611 (54) | 24,522 (47) | |
| BMI, kg/m2, median (IQR) | 26.7 (23.5–30.5) | 27.1 (23.3–31.8) | 0.047 |
| HCV serostatus, No. (%) | 94 (8.4) | 4249 (8.1) | 0.75 |
| Causes of death, No. (%) | <0.001 | ||
| Anoxia | 426 (38) | 21,939 (42) | |
| CVA | 165 (15) | 13,797 (26) | |
| Head trauma | 502 (45) | 15,161 (29) | |
| Others | 29 (2.6) | 1399 (2.7) | |
| Kidney pump, No. (%) | 509 (45) | 23,220 (44) | 0.52 |
| Cold ischemia time, median (IQR) | 14.7 (8.9–20.5) | 16.3 (11.0–22.4) | <0.001 |
| Distance, median (IQR) | 91.0 (17.2–268.8) | 69.0 (9.0–206.0) | <0.001 |
| KDPI, median (IQR) | 0.20 (0.08–0.36) | 0.43 (0.21–0.65) | <0.001 |
BMI, body mass index; cPRA, calculated panel reactive antibody; CVA, cerebrovascular accident; HCV, hepatitis C virus; IQR, interquartile range; KDPI, kidney donor profile index; KTA, kidney transplantation alone; SHKT, simultaneous heart–kidney transplantation.
Donor Characteristics
Donors of SHKT recipients were younger (median: 30 versus 39 years, P < 0.001), with more male (73.8% versus 59.9%, P < 0.001) and lower serum creatinine level (0.91 versus 1.00 mg/dl, P < 0.001) (Table 1). In SHKT donors, cold ischemia time for renal graft was shorter (median: 14.7 versus 16.3 hours, P < 0.001) with a lower kidney donor profile index (KDPI)18 (20% versus 43%, P < 0.001) (Supplemental Figure 2). The travel distance between donor and recipient hospitals was longer in SHKT (91 versus 69 miles, P < 0.001). The rate of kidney pump use was comparable between two groups (SHKT 45.4% versus KTA 44.4%, P = 0.75). In the matched cohort, donor characteristics were similar between the two groups except blood types.
Outcomes of Simultaneous Heart–Kidney Transplantation versus KTA
Early Postoperative Outcomes
In the nonmatched cohort, SHKT recipients had significantly higher 30-day mortality (SHKT 4.1% versus KTA 0.6%, P < 0.001) and kidney graft failure rate (7.0% versus 1.6%, P < 0.001) (Table 2). The length of hospital stay post-transplant was longer in SHKT (21 versus 5 days, P < 0.001). The incidence of KDGF was similar between two groups (SHKT 27.5% versus KTA 25.1%, P = 0.15). In the matched cohort, the incidence of KDGF was higher in SHKT (29% versus 10%, P < 0.001). Multivariate logistic regression analysis showed that SHKT was associated with KDGF (aOR, 4.56; 95% CI, 3.43 to 6.12; P < 0.001) (Table 3 and Supplemental Table 3). The incidence of kidney rejection before discharge was higher in SHKT recipients (2.1% versus 1.1%, P < 0.001).
Table 2.
Outcomes of simultaneous heart–kidney transplantation compared with kidney transplantation alone
| Outcomes | Nonmatched | Matched | ||||
|---|---|---|---|---|---|---|
| SHKT | KTA | P Value | SHKT | KTA | P Value | |
| n=1122 | n=52,296 | n=852 | n=852 | |||
| KDGF, No. (%) | 309 (27.5) | 13,117 (25.1) | 0.15 | 250 (29) | 86 (10) | <0.001 |
| 30-d mortality, No. (%) | 46 (4.1) | 283 (0.6) | <0.001 | 32 (3.8) | 2 (0.2) | <0.001 |
| LOS, days, median (IQR) | 21 (14–33) | 5 (4–6) | <0.001 | 20 (14–32) | 4 (3–6) | <0.001 |
| Kidney rejection, No. (%) | ||||||
| Before initial discharge | 24 (2.1) | 586 (1.1) | <0.001 | 16 (1.9) | 8 (0.9) | 0.15 |
| 6 mo post-transplant | 32 (2.9) | 2160 (4.1) | <0.001 | 24 (2.8) | 39 (4.6) | <0.001 |
| 1 yr post-transplant | 36 (3.2) | 2534 (4.8) | <0.001 | 26 (3.1) | 39 (4.6) | <0.001 |
IQR, interquartile range; KDGF, kidney delayed graft function; KTA, kidney transplantation alone; LOS, length of post-transplant hospital stay; SHKT, simultaneous heart–kidney transplantation.
Table 3.
Overall survival and graft survival in simultaneous heart–kidney transplantation and kidney transplantation alone
| SHKT versus KTA (Ref) | Nonmatched Univariable | Matched Univariable | Matched Multivariable | |||||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | P Value | HR (95% CI) | P Value | aHRa (95% CI) | P Valuea | |||
| Mortality | 1.75 (1.50 to 2.05) | <0.001 | 2.36 (1.72 to 3.23) | <0.001 | 2.65 (1.92 to 3.65) | <0.001 | ||
| Kidney graft failure | 1.56 (1.36 to 1.79) | <0.001 | 2.40 (1.82 to 3.17) | <0.001 | 2.56 (1.94 to 3.39) | <0.001 | ||
| OR (95% CI) | P Value | OR (95% CI) | P Value | aORa (95% CI) | P Valuea | |
|---|---|---|---|---|---|---|
| 30-d kidney graft failure | 4.78 (3.74 to 6.03) | <0.001 | 10.3 (4.79 to 26.8) | <0.001 | 10.9 (5.06 to 28.7) | <0.001 |
| 60-d kidney graft failure | 4.98 (4.03 to 6.10) | <0.001 | 9.84 (5.18 to 21.2) | <0.001 | 10.1 (5.32 to 21.8) | <0.001 |
| 90-d kidney graft failure | 4.36 (3.57 to 5.29) | <0.001 | 8.27 (4.67 to 16.0) | <0.001 | 8.52 (4.80 to 16.5) | <0.001 |
| KDGF | 1.14 (0.99 to 1.29) | 0.061 | 3.70 (2.84 to 4.85) | <0.001 | 4.56 (3.43 to 6.12) | <0.001 |
aHR, adjusted hazard ratio; aOR, adjusted odds ratio; CI, confidence interval; HR, hazard ratio; KDGF, kidney delayed graft function; KTA, kidney transplantation alone; OR, odds ratio; SHKT, simultaneous heart–kidney transplantation.
variable
Long-Term Outcomes
The median (interquartile range) follow-up period was 2.0 (1.0–3.8) years. In the nonmatched cohort, 2-year OS (SHKT 82.7% versus KTA 90.3%, P < 0.001) was worse in SHKT. In the matched cohort, Kaplan–Meir survival analysis showed that OS (2-year: SHKT 86.7% versus KTA 95.3%, P < 0.001) and kidney GS (2-year: SHKT 82.8% versus KTA 93.7%, P < 0.001) were inferior in SHKT (Figure 2).
Figure 2.
Survival analysis of simultaneous heart–kidney transplantation and KTA. (A) OS in heart–kidney transplantation compared with KTA in the nonmatched cohort. (B) Kidney GS in heart–kidney transplantation compared with KTA in the nonmatched cohort. (C) OS in heart–kidney transplantation compared with KTA in the matched cohort. (D) Kidney GS in heart–kidney transplantation compared with KTA in the matched cohort. GS, graft survival; OS, overall survival.
Multivariable Cox proportional hazard regression analysis showed that SHKT is associated with both mortality (aHR, 2.65; 95% CI, 1.92 to 3.65; P < 0.001) and kidney graft failure (aHR, 2.56; 95% CI, 1.94 to 3.39; P < 0.001) (Table 3 and Supplemental Tables 4 and 5). The rate of kidney rejection requiring treatment at 1-year post-transplant was lower in SHKT recipients (SHKT 3.2% versus KTA 4.8%, P < 0.001).
Mortality and Kidney Graft Failure
A total of 5115 cases of patient death (SHKT N=165 versus KTA N=4950) and 7301 cases of kidney graft failures (SHKT N=211 versus KTA N=7090) were seen in the nonmatched cohort. Mortality among SHKT recipients was seen early after transplant with significantly higher rates of death, which persisted at post-transplant 30 days (27.3% versus 5.7%, P < 0.001), 60 days (43% versus 9.2%, P < 0.001), and 90 days (48.5% versus 12.4%, P < 0.001). Significantly higher rate of kidney graft failure at post-transplant 30 days (SHKT 37.4% versus KTA 11.5%, P < 0.001), 60 days (SHKT 51.2% versus KTA 15.4%, P < 0.001) and 90 days (SHKT 56.9% versus KTA 19.7%, P < 0.001) was seen (Supplemental Table 2 and Supplemental Figure 3).
Causes of 30-day mortality were multisystem organ failure (SHKT 28% versus KTA 7.9%, P < 0.001) and infection or sepsis (SHKT 22% versus KTA 10%, P = 0.086) (Table 4). The cumulative known causes of kidney failure are shown in Table 5. The major causes of kidney graft failure in SHKT recipients were patient death (43.9%) and PNF of kidney graft (41.5%) while kidney allograft rejection (37.9%) was the most common cause of kidney graft failure in KTA followed by patient death (26%). After the removal of patients who had kidney graft failure within the first 60 days post-transplant, kidney GS was comparable between the two groups (Supplemental Figure 4).
Table 4.
Thirty-day mortality and causes in simultaneous heart–kidney transplantation and kidney transplantation alone
| Variable | SHKT | KTA | P Value |
|---|---|---|---|
| n=1122 | n=52,296 | ||
| Total deaths | 46 (4.1%) | 290 (0.55%) | <0.001 |
| Causes of death | |||
| Multisystem organ failure | 13 (28.3%) | 23 (7.9%) | <0.001 |
| Infection or sepsis | 10 (21.7%) | 33 (11.3%) | 0.086 |
| Cardiac | 8 (17.4%) | 115 (39.7%) | 0.0060 |
| CNS | 7 (15.2%) | 21 (7.2%) | 0.13 |
| Respiratory failure | 3 (6.5%) | 18 (6.2%) | 0.99 |
| Gastrointestinal system | 2 (4.3%) | 3 (1.0%) | 0.14 |
| Graft failure | 1 (2.2%) | 1 (0.3%) | 0.26 |
| Hemorrhage | 0 (0%) | 17 (5.9%) | 0.14 |
| COVID-19 | 0 (0%) | 8 (2.8%) | 0.60 |
| Others | 2 (4.3%) | 51 (17.6%) | 0.027 |
CNS, central nervous system; KTA, kidney transplantation alone; SHKT, simultaneous heart–kidney transplantation.
Table 5.
Cumulative kidney graft failures with a known cause in simultaneous heart–kidney transplantation and kidney transplantation alone
| Kidney Graft Failures | SHKT | KTA | P Value |
|---|---|---|---|
| n=82 | n=3287 | ||
| PNF | 34 (41.5%) | 431 (13.1%) | <0.001 |
| Other causes including death | 36 (43.9%) | 855 (26.0%) | <0.001 |
| BK virus | 4 (4.9%) | 97 (3.0%) | 0.31 |
| Infection | 3 (3.7%) | 182 (5.5%) | 0.46 |
| Graft thrombosis | 2 (2.4%) | 241 (7.3%) | 0.091 |
| Rejection | 2 (2.4%) | 1244 (37.9%) | <0.001 |
| Hyper acute rejection | 0 (0%) | 5 (0.2%) | 0.72 |
| Acute rejection | 1 (1.2%) | 533 (16.2%) | <0.01 |
| Chronic rejection | 1 (1.2%) | 706 (21.5%) | <0.001 |
| Recurrent disease | 1 (1.2%) | 197 (6.0%) | 0.09 |
| Surgical complications | 0 (0%) | 24 (0.7%) | 0.44 |
| Urological complications | 0 (0%) | 14 (0.4%) | 0.55 |
| Primary failure | 0 (0%) | 2 (0.1%) | 0.82 |
KTA, kidney transplantation alone; PNF, primary nonfunction; SHKT, simultaneous heart–kidney transplantation.
Subgroup Analysis of Simultaneous Heart–Kidney Transplantation Recipients
In subgroup analysis of SHKT recipients, multivariable logistic regression analysis showed that the use of pretransplant mechanical cardiac support (aOR, 2.57; P = 0.017), higher calculated panel reactive antibody (aOR, 1.76; P = 0.016), and older donor age per 10 years (aOR, 1.94; P = 0.001) was associated with PNF (Supplemental Table 6) while older recipient age per 10 years (aOR, 0.63; P = 0.006) was less likely to have PNF. Pretransplant extracorporeal membrane oxygenation (ECMO) support was associated with the higher risk of 30-day mortality (aOR, 5.55; P = 0.002) (Supplemental Table 7). Utilization of pretransplant mechanical cardiac support (aOR, 1.77; P = 0.038), recipient with dialysis at time of transplant (aOR, 1.72; P = 0.044), increased donor serum creatinine at donation (aOR, 1.34; P = 0.026), and recipient and donor gender mismatch (aOR, 1.82; P = 0.040) was also associated with the risk of 30-day kidney graft failure (Supplemental Table 8).
Discussion
The major finding of this study is that the kidney allograft outcomes in SHKT during the study period were inferior to that of KTA, despite the better quality of donor kidney as represented by lower KDPI. The most common causes of kidney graft failure in SHKT during the early post-transplant period are PNF of the kidney graft and recipient death.
Although SHKT can improve survival of advanced heart failure patients with associated kidney dysfunction,19,20 an unresolved question is when and how SHKT should be performed in patients with advanced heart failure and kidney dysfunction, without compromising organ supply for KTA candidates for whom kidney transplantation offers promising long-term survival and quality of life with a lower postoperative risk.21
Our study shows that SHKT recipients have worse short-term outcomes with a higher incidence of KDGF (matched cohort: SHKT 29% versus KTA 10%) and higher 30-day post-transplant mortality (matched cohort: SHKT 3.6% versus KTA 0.2%). This is likely multifactorial because of complexities and complications associated with two major surgeries including use of cardiopulmonary bypass, the fluctuations in the perioperative hemodynamics and fluid balance, and need for hemodynamic support in all stages of the transplant.19,22–24 Among SHKT recipients, 37% are supported by mechanical circulatory support before HT, including ECMO, intra-aortic balloon pump, or percutaneous left ventricular assisted devices.25 This trend has only increased after implementation of the new heart allocation policy in 2018, where the new policy was associated with an increased risk of mortality and renal graft failure among SHKT recipients.26 The risk of hemodynamic instability carries further in the perioperative and postoperative periods. Toinet et al. reported that preoperative dialysis and postoperative ECMO use increases the risk of mortality in SHKT patients24 which was further validated in the subgroup analysis of our cohort where use of ECMO was associated with increased risk of 30-day mortality (aOR, 5.5) and 30-day renal graft failure (aOR, 2.5). Single-center experiences by Beetz et al. reported that the history of cardiac surgery in SHKT patients is associated with developing kidney PNF, early kidney graft loss, and mortality.15 This further highlights the complexity in immediate post-transplant management of SHKT recipients and presence of various heterogeneous risk factors that help create a potentially kidney hostile milieu that may ultimately lead to significantly higher rates of PNF and renal graft loss and mortality in the early post-transplant period.
Interestingly, our results showed that after removing the initial inferior results within early (60 days) post-transplant, the overall and kidney GSs were comparable between two groups, which suggests that initial good outcomes are crucial to achieve optimal multiorgan and single-organ transplant outcomes. In the long term, the rate of death censored kidney graft failure after KTA gradually increases approximately 5% per year after the first-year post-transplant.21,27 The two major causes of kidney graft failure in KTA were allograft rejection (37.9%), followed by recipient death (26.0%). Conversely, kidney graft failures in SHKT were mainly due to PNF of kidney graft and early post-transplant mortality.11 In our study, 41.5% of SHKT patients with PNF lost the kidney graft during the follow-up period. In terms of indications of SHKT, Shaw et al. demonstrated that SHKT recipients have survival benefits over HT alone if recipients are dialysis-dependent or have decreased eGFR at transplant <40 ml/min per 1.73 m228 while the benefit of SHKT is unclear in patients with eGFR 40 ml/min per 1.73 m2 or greater. There is significant center-wide variation in the practices of listing patients for SHKT highlighted by the finding that only 30% of the SHKT candidates were on hemodialysis at the time of transplant in our cohort. In this study, patients on hemodialysis at the time of transplant had higher risk of 30-day graft failure. In multivariable analysis, new allocation system along with obese recipients, prior cardiac surgery, higher bilirubin level, pretransplant hemodialysis, and lower KDPI were identified as predictors of kidney graft failure.26 These inferior results of patient and graft outcomes further highlight the need for better patient selection under current transplant practices.
SHKT also protects both the cardiac and kidney allografts in terms of immunological and biological protection from dual-organ recipients14,29,30 and decreased progression of vasculopathy compared with HT alone.31,32 In our cohort, the rejection rate of kidney allograft at 1 year in SHKT was lower than KTA. Although HT recipients usually receive more intense immunosuppressive regimen compared with KTA, the reason for lower rate of kidney rejection could be from biological protection or from patient selection after higher mortality immediate post-transplant in SHKT recipients. On the contrary, the rate of kidney allograft rejection during the initial hospitalization post-transplant was higher in the SHKT group. This might be related to prolonged length of hospital stay with an increased chance to get a diagnostic confirmation via biopsy or due to alteration in immunomodulation practices for older and critically ill SHKT recipients (Supplemental Table 9) with a goal to decrease the risk of infection.
To avoid early and subsequent kidney graft failure after SHKT, several strategies have been proposed. This includes delayed implementation of the kidney graft after ex vivo perfusion as reported by Lutz et al.33 This allows for hemodynamic stabilization of the HT recipient, followed by kidney transplant or kidney transplant in a backup candidate. In addition, KTA after HT (KAH) has been shown to have better overall and kidney GS compared with SHKT.14 A developed form of this strategy known as a safety net was validated and functionalized in liver transplantation where recipients with nonreversible kidney dysfunction within the first year of liver transplantation are eligible for priority access to deceased KTA.34,35 Safety-net policy for KAH was implemented on June 29, 2023 and the eligibility criteria is similar to simultaneous liver and kidney, and this option would hopefully mitigate the higher than expected risk of poor renal outcomes after SHKT.36
Identification of risk factors for adverse outcomes in our study along with important findings by Wayda et al. demonstrating that SHKT would have greater benefit in younger (18–49 years) HT candidates with renal dysfunction whose probability of renal recovery was <35%11 can help formalize a uniform strategy for candidate selection for SHKT versus KAH. While understanding and using the information regarding risk factors associated with more than expected worse outcomes, we must remain vigilant about the fact that a kidney transplant in any high-risk group should not be based on absolute survival but on relative survival benefit. Therefore, our study results can help further identify a subset of patients who may benefit from either a SHKT or KAH approach, especially after introduction of safety-net policy. Any future prospective analysis, when evaluating outcomes after introduction of safety-net, would also benefit from an additional relative survival benefit approach to ensure that the scare resource like kidneys grafts is used optimally.
Limitations of this study include retrospective design using UNOS database, inability to evaluate the detailed information regarding the causes of patient's death and graft failure and the post-transplant complications, especially in AKI. Not all kidney graft failures were captured and recorded, and duration of KDGF was not available in the UNOS database. The diagnosis of the causes of kidney graft failures was relied on in the report to UNOS, and the diagnosis would vary in each transplant program and was not universally defined in this study. Propensity score matching did not account for cardiac conditions, including left ventricular ejection fraction and right-sided hemodynamics (filling pressures, vascular resistance, cardiac output, etc.) which are not available in KTA patients in UNOS database. In addition to these, the perioperative hemodynamic instability including the mechanical support and utilization of vasopressors, bleeding complications, including blood transfusions and postoperative duration of hemodialysis, or renal insufficiency, and renal recovery were not available.
In conclusion, SHKT was associated with worse kidney graft outcomes compared with KTA in the recent UNOS data which is mainly driven by significant PNF graft of a kidney graft and early postoperative mortality. More evidence is necessary to determine the optimal balance of dual organ utilization, indications of SHKT, and transplant outcomes between KTA and SHKT candidates, including implementation of a safety-net policy.
Supplementary Material
Acknowledgments
The data reported here have been supplied by UNOS as the contractor for the OPTN. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of or interpretation by the OPTN or the US Government.
Disclosures
A. Dhand reports the following: Consultancy: Eurofins Viracor, La Jolla, and Merck; Research Funding: Regeneron and Tetrapahase; and Honoraria: Merck. H. Sogawa reports the following: Ownership Interest: Pfizer. All remaining authors have nothing to disclose.
Funding
None.
Author Contributions
Conceptualization: Abhay Dhand, Kenji Okumura.
Data curation: Kenji Okumura, Kevin Wolfe.
Formal analysis: Abhay Dhand, Kenji Okumura.
Investigation: Ryosuke Misawa, Kenji Okumura.
Methodology: Abhay Dhand, Seigo Nishida, Suguru Ohira, Kenji Okumura.
Project administration: Kenji Okumura.
Software: Kenji Okumura.
Writing – original draft: Abhay Dhand, Kenji Okumura.
Writing – review & editing: Abhay Dhand, Masashi Kai, Steven Lansman, Ryosuke Misawa, Seigo Nishida, Suguru Ohira, Kenji Okumura, Hiroshi Sogawa, David Spielvogel, Gregory Veillette.
Data Sharing Statement
Anonymized data created for the study are or will be available in a persistent repository on publication. Analyzable Data. Scientific Registry of Transplant REcipients (SRTR). SRTR data are available on request.
Supplemental Material
This article contains the following supplemental material online at http://links.lww.com/KN9/A431.
Supplemental Figure 1. Covariate balance in unmatched and matched cohorts.
Supplemental Figure 2. Frequency distribution of KDPI in simultaneous heart–kidney transplantation and kidney transplantation alone.
Supplemental Figure 3. Early kidney graft survival between simultaneous heart–kidney transplantation and kidney transplantation alone in the matched cohort.
Supplemental Figure 4. Kidney graft survival between simultaneous heart–kidney transplantation and kidney transplantation alone, in matched cohort removing patients who had kidney graft failure within 30 days (A), 60 days (B), and 90 days (C).
Supplemental Table 1. Characteristics of patients with simultaneous heart–kidney transplantation and kidney transplantation alone, matched cohort.
Supplemental Table 2. Timing and early post-transplant mortality and kidney graft failure rates with simultaneous heart–kidney transplantation and kidney transplantation alone in the nonmatched cohort.
Supplemental Table 3. Factors associated with kidney delayed graft function: univariable and multivariable logistic regression analyses in the matched cohort.
Supplemental Table 4. Factors associated with patient survival: univariable and multivariable cox regression analyses in the matched cohort.
Supplemental Table 5. Factors associated with kidney graft failure: univariable and multivariable cox regression analyses in the matched cohort.
Supplemental Table 6. Subgroup analysis of factors associated with primary nonfunction of kidney graft in simultaneous heart–kidney transplantation recipients.
Supplemental Table 7. Subgroup analysis of factors associated with 30-day patient survival in simultaneous heart–kidney transplantation transplantation recipients.
Supplemental Table 8. Subgroup analysis of factors associated with 30-day kidney graft failure in simultaneous heart–kidney transplantation recipients.
Supplemental Table 9. Immunosuppression among simultaneous heart–kidney transplantation and kidney transplantation alone in the nonmatched and matched cohorts.
Supplemental Table 10. Missing variables.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Anonymized data created for the study are or will be available in a persistent repository on publication. Analyzable Data. Scientific Registry of Transplant REcipients (SRTR). SRTR data are available on request.