In this study of the US population of cirrhotic patients listed for liver transplantation, the MELD and MELDNa scores underestimate the mortality risk among 24.4% of patients with moderate ascites, an effect that persisted across the spectrum of MELD, MELDNa and serum sodium. Despite the subjective nature of ascites measurement, moderate ascites informed risk models beyond that of the MELD and MELDNa with a substantially improved waitlist mortality risk discrimination assessed by the C-statistic, IDI and NRI. It is not the intention of the authors to replace MELD or increase its subjectivity for liver allocation; instead, these results offer an opportunity to refine the risk prediction and interpretation of MELD, especially in the low-MELD spectrum. Clinically, the increased risk associated with moderate ascites can inform clinical decision-making and identify low-MELD patients who may benefit most from extended criteria donors.
The impact of ascites is most prominent at low scores, such that moderate ascites equates to the addition of 4.7 MELD points or 3.5 MELDNa points. Improvement to prognostic models is often limited by the “first-mover advantage” that is commonly witnessed in market competition. That is, the addition of a parameter to currently accepted prognostic models, whether that be MELD or MELDNa, is often at best incremental; however, we demonstrate here that the addition of this parameter is clinically significant under certain conditions. These conditions are those patients with low MELD/MELDNa and particularly among patients who are listed in high-demand, low-supply UNOS regions. In those regions, ignoring the presence of ascites underestimates the mortality risk and is associated with increased 90-day and 1-year wait list mortality. The clinical importance of this parameter is mirrored by the statistical significance (risk reclassification and NRI, improvement in the receiver operator curve and the C-statistic, and the IDI). These statistical tests convey that incorporating ascites into the risk model more accurately categorized patients who died into a high-risk profile while in individuals who did not die, it lowered their risk profile. While similar findings have been reported previously, this work extends beyond small retrospective studies and single institutions.(4
In geographic areas with heightened scarcity of available liver grafts, patients with ascites may require more aggressive monitoring and stronger consideration of extended criteria donors. Under the current MELD-based liver allocation, MELD score alone is used for prioritization of urgency for liver transplantation. Because ascites is a well known predictor of mortality with cirrhosis,(10
) it is a common, yet often unsuccessful, justification cited in petitions for exceptional priority outside the standard MELD-based allocation.(17
) The MELD score required to obtain a liver graft offer varies dramatically by UNOS region and the designated service areas within UNOS region.(20
) Without an approved petition for additional exceptional priority, our study and a smaller study of 211 cirrhotic veterans suggest that patients with ascites may be further disadvantaged in their access to transplant by approximately 4.7 MELD points when the laboratory MELD was < 21.(10
) Additionally, our study demonstrates that not accounting for the risk associated with moderate ascites results in the 8.6% misclassification in this population with limited access to liver transplant because of a MELD <21. Schaubel et al. have shown that with an increasing severity of illness as measured by MELD, there is an increasing benefit of transplantation with less ideal liver grafts as measured by the donor risk index (DRI). (22
) Given the increased risk of dying without the opportunity for liver transplantation, patients with moderate ascites could benefit from a close assessment of the relative risks and benefits of extended donor liver graft options.
Concern about the objectivity of quantifying ascites has cast doubt on inclusion of ascites in risk prediction models. While it is not the objective of the authors to incorporate ascites to an allocation system, the risk-classification data particularly in the low-MELD cohort suggests that incorporating it into clinical decision making such as improving patient selection for extended donor liver grafts may improve outcomes. Given the frequent use and availability of radiologic studies in cirrhotic patients, ascites can be easily assessed by a relatively unbiased provider, the radiologist. However, limitations exist regarding the volumetric quantification of ascites as there is no currently accepted standard or no documented clinical benefit of precise measurements. The current variability in the assessed volume (none, small, moderate) between and within each individual radiologist can lead to the misclassification of ascites volume; however, this inaccuracy in coding small ascites and moderate ascites and vice versa would underestimate the impact of this parameter on mortality. In addition, the UNOS database lacks data on medication use and precludes examination of the contribution of diuretics or salt-restriction. It is likely that most patients with ascites who are listed and cared for by transplant hepatologists would be on these medications. Regardless, the inability to control ascites such that it is absent or small portends poor short-term outcomes. Data on the cause-specific mortality is also lacking, which limits our ability to identify interventions to decrease mortality in this cohort. Future research may quantify the utility of volumetric measurements or identify more objective measures of the hemodynamic derangements in cirrhosis not accounted for by current models, such as plasma levels of aldosterone, renin, or norepinephrine, that may be collinear with ascites and importantly delineate the mortality risk.(23
In conclusion, moderate ascites informs mortality risk prediction in cirrhotic patients beyond MELD and MELDNa. Under the current MELD based liver allocation system, the presence of moderate ascites should prompt clinicians and patients to consider strategies to expand access to liver transplantation such as extended donor liver grafts.