A decline in functional status while awaiting liver transplantation is predictive of increased post-transplantation mortality

Abstract

Background:

Functional status (FS) is dynamic and changes over time. We examined how changes in FS while awaiting liver transplantation influence post-transplant outcomes.

Methods:

Data on adult liver transplants performed in the United States during the MELD era were obtained through September 2020. Patient and graft survival were compared between groups with no change or improved FS, and those with worsening FS.

Results:

Of the 90,210 transplant recipients included in the analysis, 39,193 (43%) had worsening FS, which was associated with longer waiting-list time (187 vs. 329 days, p < 0.001) and worse patient survival after liver transplant (1858 vs. 1727 days, p < 0.001). A consistent and dose-dependent relationship was observed for each 10-point decrease in Karnofsky Performance Score and post-transplant survival. Multivariable regression analysis confirmed that a decline in FS was associated with worse patient survival (HR 1.15, p < 0.001). Similar findings were observed for graft survival.

Conclusion:

A decline in FS on the waiting-list is associated with significantly greater post-liver transplant mortality in recipients. These results should be taken into consideration when allocating organs and determining transplant candidacy. Strategies to optimize FS prior to transplantation should be prioritized as even subtle decreases in FS are associated with inferior post-transplantation outcomes.

Introduction

Liver transplantation (LT) is the only curative treatment for patients with end stage liver disease (ESLD), however, the shortage of suitable donor organs continues to be problematic. With advances in pre-LT clinical care, changes in the organ allocation system, and graying of the United States population, LT recipients continue to be transplanted with higher model for end stage liver disease (MELD) scores and frequently at an older age.^1,2 In general, patients transplanted today have more advanced ESLD, greater frailty, worse functional status (FS), more sarcopenia and greater malnutrition.^3-5 In order to improve outcomes after LT, it is important to identify and optimize modifiable factors prior to LT.

Frailty, which is characterized by diminished strength, endurance, and reduced physiological function, increases an individual’s vulnerability for developing dependency and/or death.⁶ Frailty is also a significant predictor of pre-operative hospitalization⁷ and waiting-list mortality before LT.^4,8 More-over, frailty is a well-known determinant of waiting-list dropout,⁹ and may be associated with worse outcomes after LT.¹⁰ Objective assessment of frailty is essential to predict transplant outcome and avoid futile LTs. Several tools are available to assess frailty in LT candidates. They include the Fried Frailty Index, Short Physical Performance Battery, Six Minute Walk Tests, Liver Frailty Index and others.^4,8,11,12 Although a standardized pre-transplant frailty assessment is recommended by the American Transplant Society, this remains largely center-specific and is not yet standardized.¹³ Many transplant centers are short staffed and lack the expertise to routinely perform a frailty assessment on every patient.

FS, which is defined as an individual’s ability to carry out their activities of daily living, can be used as a surrogate for frailty. FS is most often assessed by the Karnofsky Performance Score (KPS). Less widely used tools include the Lansky Play–Performance Scale and the modified Easter Cooperative Oncology Group performance status.^14-16 KPS is an 11-point scale ranging from 100 (normal functioning with no evidence of disease) to 0 (deceased). FS as measured by KPS is a reliable predictor of perioperative mortality in patients with ESLD. FS assessment using KPS is the accepted standard used for required reporting to the United Network for Organ Sharing (UNOS). This assessment is performed at two time points: when a patient is added to the waiting-list and when the candidate undergoes LT.^17,18

Decline in FS on the waiting-list is associated with increased rates of waiting list dropout and pre-LT mortality.¹⁶ Worse FS at the time of LT is also associated with increased one-year mortality following LT.¹⁹ The relationship between change in FS and post-LT outcome, however, has not yet been investigated. The few publications that do analyze this relationship are largely in the non-LT geriatric population and show that a decline in FS correlates with increased mortality.^20,21 For these reasons, we conducted a secondary analysis of the UNOS database to investigate the hypothesis that worsening FS while awaiting LT is associated with inferior post-LT outcomes.

Methodology

We retrieved data from the UNOS registry on all adults who underwent deceased-donor liver transplantation between January 2003 and September 2020, with permission from the Organ Procurement Transplantation Network. The UNOS public registry contains de-identified information on various allographs transplanted within the United States, including data from donor and recipients, and excluding donor organs from prisoners. Given the significant policy changes that were implemented with the utilization of MELD score for organ allocation, we limited solely to the MELD era and excluded data before January, 2003. We also excluded patients with status 1a, multi-visceral, living donor, re-transplants or KPS that fell outside of the standard reported range (0–100).

FS was available for evaluation at two time points: 1) at the time of patient registration to the waiting-list and 2) at the time of LT. The study cohort was divided into two groups: candidates with no change or improvement in FS (the same or increased numeric value of KPS between time of the registration and time of transplant [Group I]), and candidates with worsening FS (decreased numeric value of KPS between time of the registration and time of transplant [Group II]).

A comparison was then performed between Groups I and II. Variables evaluated included demographics (age, gender, and body mass index [BMI] both at the time of listing and transplantation), race/ethnicity (African American, Asian, Caucasian, Hispanic), etiology of ESLD, length of time on the waiting-list, graft survival (in days), laboratory values both at the time of waiting-list addition and at the time of LT (serum albumin, bilirubin, creatinine, sodium levels), MELD score both at waiting-list addition and at LT, presence of ascites or hepatic encephalopathy (HE), transjugular intrahepatic portosystemic shunt (TIPS) placement, history of spontaneous bacterial peritonitis (SBP), portal vein thromboses (PVT) at the time of waiting-list addition and LT, diabetes mellitus (DM), preoperative dialysis, KPS at listing, and donor risk index (DRI).

Subgroup analysis stratified by hepatocellular carcinoma (HCC) was also performed across Group I and Group II given that while HCC candidates have greater rates of waiting-list dropout, it is currently thought this is attributable to disease progression outside of accepted transplant criteria, rather than worsening sarcopenia, malnutrition, or FS.^22,23 Subgroup analysis was also performed limiting just to transplant recipients in Group II to better quantify how much of a decline in FS was clinically significant. Between group comparisons were made between recipients with −10, −20 and −30 or greater decline in FS.

Statistical analysis

Recipients with better or same functional status FS (Group I) were compared statistically to those with worse FS (Group II) statistically for multiple factors, including demographics, waiting-list characteristics, medical comorbidities, transplantation characteristics, donor characteristics, and outcomes. Bivariate comparisons were performed for log-transformed Kaplan–Meier Survival curves, in addition to Student t test, Wilcoxon sign rank test, chi-square test, or Fisher’s exact test as appropriate. Multivariable logistic regression modeling was used to explore the relationship between worsening FS after adjusting for potential confounders as determined by prior literature and results of the bivariate analysis (variables were included in the multivariable model if they were statistically significant at p < 0.10). The results of the final logistic regression model were presented as adjusted odds ratios accompanied by 95% confidence intervals (95% CI), and weighted by propensity scores, for HCC and non-HCC subsets. Five year patient and graft survival were estimated by adjusted Kaplan–Meier method, for HCC and non-HCC subsets. The log-rank test was used to compare differences in survival. Cox proportional hazards models were used to assess factors associated with patient and graft survival. Independent predictive factors for post-transplant patient and graft survival. The results of the Cox models were presented as adjusted hazard ratios accompanied by 95% CI.

Because of significant differences in baseline characteristics of groups I and II subsets, we used propensity scores for 1:1 matching of groups I and II patients. All variables were different (p < 0.20) between groups I and II patients in the bivariate analysis were included to calculate the propensity scores. Thus, propensity scores were calculated using age at listing, sex (reference group-female), and MELD at listing. Next a Cox proportional hazard model was accessed for other key variables including: race/ethnic group (reference group-white), etiology of ESLD (nonalcoholic steatohepatitis [NASH]/cryptogenic, cholestatic, hepatitis B [HBV], HCC, hepatitis C [HCV]), PVT at the time of LT, portal hypertension manifestations (including ascites and HE grade 2 and above), DM, DRI, and dialysis at the time of LT. Spearman’s Correlation Coefficients were generated to determine the monotonicity between multiple variables.

All statistical tests for significance were 2-sided, and a significance level of p < 0.05 was considered significant. No significance level adjustments for multiple analyses were imposed. All data set manipulation and statistical analyses were performed with SAS (version 9.4; Cary, NC). The study was approved by the Institutional Review Board at the Penn State Hershey Medical Center.

Results

Between January 1st, 2003 and September 30th, 2020, 116,565 adult candidates underwent LT in the US. After the exclusion of 26,365 candidates, 90,210 LT recipients were included in the final analysis. Exclusions included: 506 (0.4%) for 1a status, 6499 (5.6%) multi-visceral transplantations, 4689 (4.0%) living donor LT recipients, 6621 (5.7%) re-transplantations, and 8040 (6.9%) missing information (Fig. 1). Among included recipients, 51,017 (57%) had the same or improved FS (Group I), and 39,193 (43%) had worsening FS (Group II). Actual KPS score at waiting-list registration as well as change in KPS score between waiting-list registration and LT are provided in Table 1 and Figures S1 and S2.

Figure 1.

Study Enrollment. A total of 90,210 adult liver transplant recipients were included in the final analysis during the MELD era through September 2020

Table 1.

Comparison of baseline characteristics of patients with the same or improved FS (Group I) and decline in FS (Group II)

	Group I (n = 51,017; 57%)	Group II (n = 39,193; 43%)	p-value
Demographics
Age mean (SD)
Age at listing, years	53.8 (10.7)	54.5 (10.3)	<0.001
Age at transplant	54.3 (10.8)	55.4 (10.2)	<0.001
BMI, median (IQR)
BMI at listing, kg/m2	28.3 (7.7)	28.43 (7.66)	<0.001
BMI at transplant, kg/m2	27.9 (7.7)	28.01 (7.85)	0.017
Sex and Race/ethnlclty, n (%)
Male sex	34,169 (67.0)	25,812 (65.9)	0.001
Race/ethnicity
African American	4709 (9.2)	3511 (9.0)	0.159
Asian	2384 (4.7)	1644 (4.2)	0.001
Caucasian	36,115(70.8)	27,537 (70.3)	0.083
Hispanic	7070 (13.9)	5953 (15.2)	<0.001
Etiology of ESLD, n (%)
Alcohol	9015 (17.8)	6055 (15.4)	<0.001
Autoimmune	1235 (2.4)	970 (2.4)	0.848
Cholestatic	2845 (5.5)	2589 (6.6)	<0.001
HBV	899 (1.8)	587 (1.5)	0.002
HCV	11,501 (22.5)	8936 (22.8)	0.362
NASH/Cryptogenic	7355 (14.4)	6157 (15.7)	<0.001
Malignancy except HCC	11,247 (24.6)	9886 (24.6)	<0.001
HCC	10,679 (21.3)	9420 (23.5)	<0.001
MELD
MELD, median (IQR)
At listing	18.0 (16.0)	17.0 (11.0)	<0.001
At transplant	20.0 (16.0)	22.0 (16.0)	<0.001
Perioperative Times in Days, mean (sd)
Waiting-list time	187 (369)	329 (562)	<0.001
Patient survival time	1859 (1888)	1727 (1756)	<0.001
Graft survival time	1865 (1654)	1736 (1504)	<0.001
Clinical Conditions, n (%)
DM	12,933 (25.8)	11.084 (27.6)	<0.001
PVT	2753 (5.5)	2199 (5.5)	0.883
SBP	4029 (8.1)	2824 (7.0)	<0.001
Dialysis (preoperative)	6565 (13.1)	6133 (15.3)	<0.001
Portal Hypertension, n (%)
Ascites > grade 2 at listing	14,618 (29.2)	13,030 (32.5)	<0.001
Ascites > grade 2 at transplant	14,690 (29.3)	13,176 (32.8)	<0.001
HE > grade 2 at listing	5776 (11.5)	4927 (12.3)	0.001
HE > grade 2 at transplant	5888 (11.8)	4997 (12.5)	0.002
TIPS, n (%)
At listing	4492 (9.0)	3650 (9.1)	0.540
At transplant	5102 (10.2)	4847 (12.1)	<0.001
DRI, mean (sd)
DRI	1.75 (0.39)	1.74 (0.39)	0.010
KPS, median (IQR)
At listing	60.0 (40.0)	70.0 (20.0)	<0.001
At transplant	70.0 (40.0)	40.0 (40.0)	<0.001
Change between listing and transplant	0 (10.0)	−20.0 (20.0)	<0.001
Laboratory Value, median (IQR)
INR, at listing	1.5 (4.0)	1.4 (0.6)	<0.001
INR, at transplant	1.6 (0.9)	1.7 (1.0)	<0.001
Serum albumin, at listing	3.1 (0.9)	3.0 (0.9)	<0.001
Serum albumin, at transplant	3.1 (1.0)	3.1 (1.0)	0.313
Serum bilirubin, at listing	2.9 (5.8)	2.7 (4.4)	<0.001
Serum bilirubin, at transplant	3.0 (6.8)	4.0 (9.3)	<0.001
Serum creatinine, at listing	1.50 (0.9)	1.0 (0.6)	<0.001
Serum creatinine, at transplant	1.09 (0.90)	1.10 (1.0)	<0.001
Serum Sodium, at listing	137.0 (6.0)	137.0 (6.0)	0.008

BMI, body mass index; DM, diabetes mellitus; DRI, donor risk index; FS, functional status; HBV, hepatitis B; HCC, hepatocellular carcinoma; HCV, hepatitis C; HE, hepatic encephalopathy; INR, international normalized ratio; IQR, Interquartile Ranges; KPS, Karnofsky Performance Score; MELD, Model for End Stage Liver Disease; NASH, nonalcoholic steatohepatitis; PVT, portal vein thrombosis; SBP, spontaneous bacterial peritonitis; sd, standard deviation; TIPSS, transjugular intrahepatic portacaval stint shunt.

In general, Groups I and II were clinically similar across baseline characteristics with several notable exceptions. While recipients in Group II had a lower MELD score at the time of addition to the waiting-list (p < 0.001), MELD score worsened while awaiting LT and became significantly greater than Group I at the time of LT (p < 0.001). Candidates in Group II had longer waiting list times (187 vs. 329 days, p < 0.001) as well as shorter post-operative patient (1859 vs. 1727 days p < 0.001) and graft survival (1865 vs. 1736 days p < 0.001) (Fig. 2 and S3).

Figure 2.

Postoperative Patient Survival: Comparison between Group I (same or improved functional status) and Group II (decline in functional status). Recipients with a decline in functional status while awaiting liver transplantation had the worse post-transplant survival.

A Spearman’s Correlation analyses for variables included in the proportional hazards model showed a mild positive correlations between worsening of FS and KPS at listing (ρ_s = 0.32), FS/HCC and KPS at listing (ρ_s = 0.38), HE and ascites (ρ_s = 0.31) as well as NASH and diabetes (ρ_s = 0.22). There also was a negative correlation between ascites and KPS at listing (ρ_s = −0.21), NASH and cholestatic (ρ_s = −0.11), HCV and cholestatic (ρ_s = −0.13), HCC and NASH (ρ_s = −0.22), HCC and cholesteric (ρ_s = −0.14), HCC and HCV (ρ_s = −0.29), HCC and dialysis preoperative (ρ_s = −0.15). All other Spearman’s Correlations were ±0.10 (Table S1).

Univariable and multivariable regression analyses demonstrated that a decline in FS was associated with worse patient (HR =1.11 and 1.15, p < 0.001 respectively) and graft survival and (HR = 1.10 and 1.12, p < 0.001 respectively) (Tables S2 and S3). Other variables identified as independent predictive factors for patient and graft survival were African American race (HR = 1.17 and 1.22, p < 0.001 for both), PVT at the time of LT (HR = 1.16 and 1.17, p < 0.001 for both), HCV (HR = 1.13 and 1.12. p < 0.001), HE > grade 2 (HR = 1.11 and 1.12, p < 0.001 for both), DRI (HR = 1.48 and 1.58, p < 0.001), need for preoperative dialysis (HR = 1.32 and 1.26, p < 0.001), and HCC (HR = 1.40 and 1.29, p < 0.001 for both) (Tables S2 and S3).

Group II analysis by amount of functional status decline

A dose-dependent relationship was found between FS decline and post-transplant patient and graft survival (Fig. 3 and S4). The lowest post-transplant survival was observed for recipients whose FS declined by 30 points or greater while awaiting LT, however, even a decline in FS by 10 points was clinically significant in predicting post-transplant survival.

Figure 3.

Group II analysis by amount of functional status decline. A dose-dependent relationship was found between functional status decline and post-transplant and graft survival. The lowest post-transplant survival was observed for recipients whose functional status declined by 30 points or greater while awaiting transplantation, however, even a decline by 10 points was clinically significant in predicting post-transplant survival

HCC recipients vs. non-HCC recipients

Product limits of the non-HCC subset demonstrated that overall, recipients with same or improved FS had better long-term survival (Fig. 4 and S5). For recipients with HCC, those with a decline in FS had the lowest survival. Using weighted product limits of HCC and non-HCC, the same or improved FS group had poorer survival, in both subsets. The multivariable regression analysis stratified by HCC status demonstrated the same trend: a decline in FS was associated with worse patient and graft survival (HR = 1.09 and 1.08, p < 0.001 for both).

Figure 4.

Postoperative Patient Survival: Comparison between Subgroups-HCC/non-HCC status with same or improved functional status and decline in functional status. Recipients with a decline in functional status had the worst outcomes, both in the presence or absence of HCC

Discussion

This is the first study to evaluate the relationship between change in FS while awaiting LT and post-LT outcome. Nearly half of subjects in this large study of American adults who underwent non-urgent LT between 2003 and 2020 had a decline in FS while awaiting LT. Independent of other factors, recipients whose FS declined had an increased hazard of death and/or graft loss at one, three and five years after LT when compared to recipients whose FS did not change or even improved while on the waiting-list. Our results further demonstrate the utility of routinely assessing FS, building on previous reports that FS assessed at a single time point is a predictor of adverse outcomes after LT, by demonstrating that FS is dynamic, and changes in most candidates between addition to the waiting-list and LT. More-over, we demonstrate that while a large decline in FS is highly predictive of greater post-transplant mortality, even a subtle decline in FS, including a decrease in KPS by as little as 10 points, can lead to inferior post-transplantation outcomes.

The results of this study have significant practical implications. In combination with other variables, changes in FS in candidates on the waiting-list can be used for decision making regarding suitability for LT. FS is routinely assessed during the evaluation process. Changes in FS provide a “big picture” of a candidate’s overall clinical condition and resilience, each of which can affect post-operative outcomes.¹⁵ In LT candidates, improvement in both muscle strength, endurance, and nutrition are crucial to improve a patient’s functionality.^24,25 There are several small studies evaluating the importance of improving the FS of LT candidates prior to LT. Roman et al.²⁶ performed a randomized, unblinded study including 20 subjects with a history of decompensated cirrhosis. They demonstrated that subjects who underwent a 12-week exercise program, involving three 1-h treadmill or bicycle activity sessions per week, had a significant improvement in 6-min walk test in comparison to controls.²⁶ Similar results have been demonstrated by Debette-Gratien et al.,²⁷ who found that in addition to improvement in 6-min walk test, subjects that participated in an exercise program demonstrated improved oxygen consumption and muscle strength. Several other studies have demonstrated that prehabilitation can improve the overall FS of patients with early-stage cirrhosis and low MELD scores.^28-31 How prehabilitation before LT affects postoperative morbidity and mortality in patients with ESLD has not been investigated but remains an interesting area for future research.

We found that while LT recipients who experienced a decline in FS initially had slightly lower MELD scores at waiting-list registration, they had both longer waiting-list times and greater increases in MELD score while awaiting LT. While our study is unable to assess this temporal relationship and determine if greater waiting-list times allowed for more time for a candidate to deteriorate clinically versus clinical deterioration leading to a longer wait prior to LT suitability, this is nonetheless important to highlight and offers an intriguing avenue ripe for future prospective study. This is especially clinically relevant in light of current organ allocation policy which has led to longer waiting-list times for candidates with low MELD scores.

The relationship between FS and outcomes in patients with HCC has been evaluated, but not in the LT setting. In a retrospective evaluation, Hsu et al.³² demonstrated that FS, based on a modified Barcelona Clinic Liver Cancer scoring system, was an accurate predictor for long-term survival in patients with HCC. Our study demonstrated that LT recipients with HCC and a decline in FS had the lowest patient and graft survival in the entire population included in this evaluation. It is well known that despite earlier transplantation, candidates with HCC have poorer outcomes in comparison to non-HCC patients.^33,34 While the majority of early deaths after LT in HCC recipients are due to aggressive HCC recurrence, it is reasonable to postulate that a decline in FS may also play a role. A decline in FS in this subpopulation, that usually has the least advanced hepatic disease with lower MELD sores and less portal hypertension, has significant predictive value and should be considered during candidate evaluation.

This study has several limitations inherent to the design which retrospectively analyzes a large national database and can only demonstrate trends and associations, not causality. Another limitation is the inherent structure of large databases. UNOS is a national database with more than two-hundred participating centers. Information gathered from centers must be manually entered. This is a cause of significant concern regarding data quality due to the possibility of misclassification errors during data entry. In addition, a number of potentially important variables such as liver frailty index, specific characteristics of postoperative complications, type of perioperative therapy, and other potentially useful parameters are not included in the UNOS database. There is also the possibility that some confounding factors that could affect outcome were not taken into consideration. Finally, the statistical significance demonstrated in a large database might not have clinical relevance because the large sample size yields extremely high statistical power for detecting small effects.

In conclusion, we found that nearly half of LT recipients have a decline in FS while awaiting liver transplantation. This is important because a decline in FS while on the waiting-list is associated with markedly worse patient and graft survival after LT. Candidates whose FS worsens while awaiting LT have greater progression of liver disease than those whose FS did not either change or improve. Combining change in FS with current organ allocation practices may allow for greater discernment of post-operative outcomes and better selection of the ideal LT candidate. Further studies are needed to determine the role of prehabilitation prior to LT in improving not only pre-LT outcomes but more importantly, long-term outcomes following successful LT, such as patient and graft survival and health-related quality of life.