In the waiting line for liver transplants: Women remain disadvantaged

Access to liver transplantation suffers from a persistent and unacceptable gender gap, with female candidates on the wait list being much less likely to receive a transplant and facing a higher risk of dying than their male counterparts, according to an expert.

“There are many reasons for this, including aspects of both the organ allocation and distribution policies,” such as the factoring in of creatinine in the Model for End-Stage Liver Disease (MELD) score and differences in body size, said Dr Elizabeth Verna of Columbia University in New York, US, who spoke at the American Association for the Study of Liver Diseases virtual annual meeting.

In the US, the current system used for allocating deceased donor livers for transplantation is based on the MELD score, which was established to form an objective and fair system that prioritizes illness without bias. However, Verna noted that for any two patients with the same MELD or MELD-Sodium(Na) score currently on the wait list, access to transplant is disproportionate, as driven by sex.

Soon after the score’s adoption in 2002, it was acknowledged that MELD might have inadvertently exacerbated the sex-based disparities in transplant outcomes. This was reported in a 2008 study comparing 4 years of wait-list candidates prior to the implementation of MELD to 4 years post. Women had a new 30 percent increase in odds of dying or becoming too sick for liver transplantation and significantly lower likelihood of receiving a liver transplant within 3 years compared with men. [JAMA 2008;300:2371-2378]

Since the report, the gender gap in wait-list outcomes and mortality risk has been demonstrated multiple times by different groups. [Am J Transplant 2010;10:2658-2664; JAMA Surg 2020;155:545-547]

“When plotted out over time, it is clear that although there have been tweaks in the MELD score to address some of its insufficiencies for some groups of patients, there’s been no change in sex-based disparities in terms of access to transplantation or rates of transplant comparing women to men,” Verna said.

Imperfect estimate

How the MELD score puts women at a disadvantage has something to do with using creatinine to estimate kidney function.

Verna pointed out that serum creatinine values in men and women are not directly comparable, given that the relationship between estimated glomerular filtration rate (eGFR) and serum creatinine is influenced by multiple variables such as age, race, and also sex.

Indeed, early data showed that a GFR of 60 correlated with a serum creatinine level of 1.3–1.5 mg/dL in White men and 1.4–1.8 in Black men as opposed to 1.0–1.2 in White women and 1.1–1.4 in Black women. The differences between men and women widened as kidney dysfunction progressed. Because muscle mass influences creatinine and women have lower levels of muscle mass than men, women’s creatinine was consistently lower at all ranges of measured GFR. [Ann Intern Med 1999;130:461-470]

“Therefore, women accrue 1–3 fewer MELD points from serum creatinine and starting at a later stage of kidney dysfunction than men with the same eGFR,” Verna said.

Size mismatch

Another factor at play in the sex-based disparities in transplant access is body size, particularly height, she added.

In a 2010 study, a group of researchers noted that female liver transplant candidates on the wait list had shorter stature. Adjusting for MELD score revealed a 19-percent increase in the risk of wait-list mortality among women, with the excess risk persisting after controlling for other factors known to contribute to wait-list mortality. However, further adjustment for height attenuated much of the risk increase, suggesting that height was an important mediator of the relationship between sex and wait-list mortality.  [Am J Transplant 2010;10:2658-2664]

A separate study showed that 166 cm or about 5’5” was the height below which people were at significantly higher risk of either dying or being delisted on the transplant list and had lower rates of transplantation. Not surprisingly, almost three-fourths of women were below this height cutoff, which put them at heightened risk of wait-list mortality. [Am J Transplant 2020;20:852-854]

The most direct reason that height would contribute so significant to wait-list outcomes, according to Verna, is that size mismatch is a very common reason to have liver offers declined. A substantial proportion of livers are just too large to be transplanted into smaller recipients.

Altogether, multiple factors—geographic region, MELD score, anthropometrics, and liver measurements—contribute to a 25-percent greater risk of wait-list mortality for women versus men. [JAMA Surg 2020;155:e201129]

Closing the gap

Verna believed that urgent action should be taken to implement pragmatic policy changes to address the multiple sources of the gender-based disparity in access to liver transplantation. “Continued refinement in allocation, prioritization, and distribution policies … is essential to improving equity.”

Several suggestions have been laid out over time, and the first thing is to fix the MELD score-based prioritization and allocation. According to Verna, this can be done by having a more accurate measure of kidney function, substituting creatinine for eGFR, adding points for female gender or height, or perhaps going back to the drawing board and creating a new MELD score.

Figuring out a way to preferentially get smaller grafts to either women or people with smaller stature can also go a long way towards reducing the gender disparities in liver transplantation access. Women should also be prioritized for paediatric donors and the use of split liver grafts be increased.

Finally, “more work is needed to understand the impact of less tangible forces, including implicit bias in organ offer acceptances, and upon healthcare delivery upstream of transplant listing,” Verna stated.

“Disparities in our system are likely to persist without attempts to address the larger societal issues that also significantly impact the care of these patients prior to liver transplant evaluation,” she said.