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U.S. women were 8.6% more likely than men to die while awaiting a liver transplant and 14.4% less likely to receive a deceased-donor liver transplant (DDLT), a large cohort study revealed.
The results indicate that any decrease in longstanding sex-based disparities in liver allocation may need a comprehensive approach that extends beyond the geographic factors currently under consideration by the transplant community, said Jayme E. Locke, MD, MPH, of the University of Alabama at Birmingham, and colleagues.
“Our findings suggest that the MELD [model for end-stage liver disease] score does not accurately estimate disease severity in women and that the lack of consideration of candidate anthropomorphic and liver measurements in the current allocation system may have a greater association with the sex disparity in liver allocation than geographic factors,” the researchers wrote in their study online in JAMA Surgery.
Therefore, proposed policies for attenuating geographic disparities alone may not be enough to attenuate existing sex-based imbalances in liver transplants, the team added.
Using data from the Scientific Registry of Transplant Recipients, the investigators looked at 81,357 adults wait-listed just for liver transplants according to figures from the Organ Procurement and Transplantation Network collected from June 2013 to March 2018.
Of these, 36.1% were women and 63.9% were men, with an overall mean age of about 55; about 85% in both groups were white. Women more often had undergone previous abdominal surgery (55.6% vs 36.6%, P<0.001), less commonly had hepatocellular carcinoma (7.3% vs 13.5%, P<0.001), and had consistently lower anthropometric and liver measurements as determined by body surface area and estimated liver volume and weight.
Of the 8,827 individuals who died on the waiting list, 3,615 (41%) were female and 5,212 (59%) were male (P<0.001); after adjustment, however, women had an 8.6% greater risk of wait list mortality compared with men (adjusted HR [aHR], 1.09; 95% CI, 1.05-1.14), Locke and co-authors reported.
Similarly, for the likelihood of receiving a DDLT, the analysis showed an aHR for females of 0.86 (95% CI 0.84-0.88), the team said.
In the geographic domain, the organization of organ procurement was the only variable significantly associated with increased disparity between female sex and wait-list mortality (aHR 1.22, 95% CI 1.09-1.30).
While geographic location was also strongly associated with increased disparities in wait-list mortality (22.8%), anthropometric and liver metrics and laboratory MELD scores had more statistically significant correlations, accounting for 125.8% and 50.1% of the sex-based inequity, respectively. “Thus, size mismatch between the donor and intended recipient and incorrect assessments of liver disease severity were more strongly associated with the observed sex disparity in wait-list mortality than local supply of organs,” the researchers wrote.
For DDLT, the associations with geographic differences were not statistically significant and accounted for only 3.9% of sex-based disparity, whereas candidates’ anthropometric and liver measurements (49%) and MELD score-determined liver disease severity (10.3%) had the strongest associations, Locke and co-authors reported.
“We propose that a better course of action is to simultaneously address the attributes of the existing allocation system that were most strongly associated with increased sex disparities in wait list mortality and DDLT in our study: the MELD score and candidate anthropomorphic and liver measurements,” the investigators wrote. “Findings from our study support such process improvement in liver allocation.”
In an accompanying invited commentary titled “Sex Does Matter in Liver Allocation — Time to Address Existing Sex-Based Disparities,” Willscott Naugler, MD, and Susan Orloff, MD, both of Oregon Health and Science University in Portland, pointed out that sex-based disparities in solid organ transplant exist in every studied phase of transplant medicine, from patient access and outcomes to the physicians performing the operations, and urged that these inequities be quickly addressed.
“It is easy to agree with the authors’ suggestion that fixing sex disparities will take more than working on the picture-dominating issue of geographic inequities,” Naugler and Orloff wrote, adding that still more adjustments may be required.
For one thing, the underestimation of renal function by creatinine measurements in women has long disadvantaged women waiting for liver transplants. “Not only does this fact lead to less access while listed, but it also means women are relatively sicker than men when they receive transplants, likely leading to a subtle worsening of transplant outcomes,” the editorialists continued, adding that a simple correction to the allocation MELD score (as was done with the addition of sodium in 2016) could take care of this problem.
Another way to mitigate the disparity, Naugler and Orloff suggested, would be to allow women of small stature, who are currently bypassed for larger livers, to access pediatric livers’ at the same time, while liver splits (where a single deceased donor liver is divided into right and left portions that are implanted into two recipients simultaneously) could be ramped up to increase contributions to the pediatric pool.
There are also sociocultural elements that favor men over women for organ transplant, the editorialists noted. For example, a woman’s traditional role as caretaker might lead a female patient to decline a transplant, even when one is available. “Similarly, clinicians have been shown to have biases against women both in referral for transplant evaluation and listing. These realities cannot be fixed with changes to the MELD score, and we must be mindful not to let such notions distract from the essential hard work of creating long-lasting cultural changes that underpin a true path forward,” Naugler and Orloff wrote.
Echoing the editorialists’ sentiments in another commentary, a Viewpoint titled “Time for Action to Address the Persistent Sex-Based Disparity in Liver Transplant Access,” Elizabeth C. Verna, MD, MS, of Columbia University Irving Medical Center in New York City, and Jennifer C. Lai, MD, MBA, of the University of California San Francisco, noted that in 2018 women on the wait list had an 11% decreased rate of DDLTs compared with men.
“It has been known for more than a decade that women are disadvantaged on the liver transplant waiting list, with an increased risk of death and a decreased probability of deceased donor liver transplant compared with men,” Verna and Lai wrote. “Despite this knowledge, there has been no effective national push to implement evidence-based systematic changes and thus no improvement in waiting list outcomes for women.”
Verna and Lai pointed to two key contributing factors that could be addressed: The first is the underestimation of kidney dysfunction by the measure of serum creatinine levels, but substituting estimated glomerular filtration rate for serum creatinine has been seen to significantly improve the ability of MELD score to predict wait-list mortality, especially among women, thereby eliminating an important proportion of sex-based inequity, the Viewpoint writers said.
The second addressable factor, they continued, relates to women’s smaller body size, with 72% versus 9% of men falling below the optimal height cutoff of 166 cm (about 65.4 inches). Women who access pediatric livers, however, experience the same wait-list mortality as men, a 2018 study found.
Assuming an access to DDLTs equal to men’s, the deaths of more than 800 women over the past decade may have been prevented, Verna and Lai calculated. “It is now time to move the debate from ongoing documentation of the disparity to discussing which concrete changes should be pursued first and how success will be measured.”
Study limitations, Locke and co-authors noted, included the reliability and accuracy of variables captured by the Organ Procurement and Transplantation Network. Moreover, other factors not routinely captured by the network may have been associated with disparities in allocation or may have confounded the findings specific to sex. In addition, the team said, variances of estimates derived from the study’s inverse odds ratio weighting can be wider than in other mediation methods, and the study may not have detected smaller mediating factors such as geographic factors.
Locke reported financial relationships with Sanofi and Hansa Medical; a co-author reported financial relationships with CareDx, Natera, and Veloxis.
Naugler and Orloff reported no conflicts of interest.
Verna reported financial relationships with Salix Pharmaceuticals and Gilead Sciences. Lai reported financial relationships with Axcella Health, BioMarin, Ambys Medicines, Pliant Therapeutics, and Genentech, and grants from the National Institutes of Health.
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