Highlight
- The Modified Frailty Index (mFI-5) stratifies liver transplant recipients into distinct frailty categories associated with differential morbidity and mortality risks.
- Moderate and severe frailty are linked to significantly increased 30-day postoperative morbidity and rejection rates.
- Severe frailty predicts higher long-term mortality up to five years post-transplant, while moderate frailty impacts short-term but not long-term survival.
- Integration of frailty assessment into pretransplant evaluation could enhance risk stratification and perioperative management strategies.
Study Background
Liver transplantation remains the definitive treatment for many patients with end-stage liver disease; however, postoperative outcomes vary widely due to patient heterogeneity. Frailty—a state of decreased physiologic reserve and increased vulnerability—has emerged as a critical determinant of adverse outcomes across various surgical populations. Despite growing recognition, the optimal method to quantify frailty for liver transplant candidates and its prognostic implications remain underexplored. This multicenter cohort study seeks to validate the 5-variable Modified Frailty Index (mFI-5) as a tool for predicting morbidity and mortality after orthotopic liver transplantation, addressing unmet needs in patient selection and perioperative planning.
Study Design
This retrospective cohort study utilized data from the TriNetX US Collaborative Network registry encompassing liver transplant recipients from 2015 to 2025. Adult patients who underwent orthotopic liver transplantation were included and categorized into three frailty groups based on their mFI-5 scores: nonfrail (0-1), moderately frail (2), and severely frail (≥3). Propensity score matching adjusted for baseline demographics, comorbidities, and Model for End-Stage Liver Disease (MELD) score components to reduce confounding.
Primary outcome measured was 30-day postoperative morbidity, defined via a composite endpoint including complications. A sensitivity analysis further expanded the composite endpoint to incorporate infections and surgical complications. Secondary outcomes involved all-cause mortality at 90 days, 1 year, 3 years, and 5 years, as well as incidences of acute rejection and graft failure.
Key Findings
Among 13,408 recipients analyzed, 4,667 were nonfrail, 4,987 moderately frail, and 3,751 severely frail. Propensity matching yielded 2,678 and 1,782 matched pairs for mFI-5 score 2 and ≥3 comparisons, respectively.
Statistical analyses showed elevated composite 30-day morbidity rates in both frail groups compared to matched nonfrail controls: 55.9% vs. 49.1% for moderately frail (OR 1.32, 95% CI 1.20-1.44) and 57.4% vs. 49.3% for severely frail (OR 1.39, 95% CI 1.24-1.54). The expanded composite endpoint confirmed these findings, underscoring frailty’s association with postoperative complications.
Contradictorily, frail patients exhibited lower 90-day mortality risk (moderate frailty HR 0.54, 95% CI 0.39-0.76; severe frailty HR 0.51, 95% CI 0.34-0.75), suggesting that initial postoperative survival may be influenced by selection biases or perioperative care variations. However, at five years, severely frail patients demonstrated significantly higher mortality (HR 1.29, 95% CI 1.07-1.54), whereas moderately frail survivors showed no difference from nonfrail controls long term.
Additionally, frailty correlated with increased rejection and graft failure rates, highlighting its role in immune vulnerability and transplant outcomes.
Expert Commentary
The findings of Abuassi et al. reinforce the clinical utility of the mFI-5 as a pragmatic, easily implemented frailty measure in the liver transplant setting. Its predictive capacity for both early morbidity and long-term survival supports incorporation into multidisciplinary transplant evaluations. This aligns with emerging consensus that biological age and physiologic reserve—captured by frailty metrics—should complement traditional severity scores like MELD.
Nevertheless, the study’s retrospective design and reliance on registry data may limit granularity regarding socioeconomic factors, nutritional status, and functional assessments such as gait speed or handgrip strength. The paradoxically reduced short-term mortality in frail patients could reflect survivor bias or more intensive management and warrants prospective validation.
Mechanistically, frailty likely reflects cumulative deficits affecting inflammation, immune function, and organ resilience, predisposing recipients to complications and impaired graft tolerance. Future research integrating frailty with biomarker profiles and dynamic functional testing could refine risk stratification.
Conclusion
This large multicenter cohort study demonstrates that the Modified Frailty Index is an effective stratification tool for assessing risk of short- and long-term adverse outcomes after liver transplantation. Moderate and severe frailty increase postoperative morbidity and rejection likelihood, with severe frailty additionally predicting elevated long-term mortality. These findings advocate for routine frailty screening to inform candidacy, optimize prehabilitation strategies, and tailor postoperative care. Further prospective studies are needed to validate frailty-guided interventions that could improve transplant success and patient survival.
Funding and ClinicalTrials.gov
The study was conducted using the TriNetX US Collaborative Network data. No specific funding or clinical trial registration was reported.
References
1. Abuassi M, Turner T, Westein R, et al. Modified Frailty Index and outcomes after liver transplantation: A multicenter cohort study. Surgery. 2026 May 15;195:110235. PMID: 42139821.
2. Lai JC, et al. Frailty in liver transplantation: An emerging outcome predictor. J Hepatol. 2017 Nov;67(5):1053-1065.
3. Englesbe MJ, et al. The Michigan Surgical Home and Optimization Program: Protocol and early results. J Am Coll Surg. 2015 Sep;221(3):660-667.
4. McAdams-DeMarco MA, et al. Frailty and immune function in kidney transplant recipients. J Am Soc Nephrol. 2015 May;26(5):1228-1239.
