Gender disparity and MELD in liver transplantation

Gender, renal function, and outcomes on the liver transplant waiting list: Assessment of revised MELD including estimated glomerular filtration rateJournal of HepatologyVol. 54Issue 3PreviewThe Model for End-Stage Liver Disease (MELD) allocation system for liver transplantation (LT) may present a disadvantage for women by including serum creatinine, which is typically lower in females. Our objectives were to investigate gender disparities in outcomes among LT candidates and to assess a revised MELD, including estimated glomerular filtration rate (eGFR), for predicting waiting list mortality. Full-Text PDF To the Editor: We read with great interest the paper by Myers et al. [[1]Myers R.P. Shaheen A.A. Aspinall A.I. Quinn R.R. Burak K.W. Gender, renal function, and outcomes on the liver transplant waiting list: Assessment of revised MELD including estimated glomerular filtration rate.J Hepatol. 2011; 54: 462-470Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar], recently published in Journal of Hepatology, regarding the disparities between males and females in the MELD-based allocation system for liver transplantation. The authors found that women are disadvantaged under MELD, which may be attributable to the use of serum creatinine (Cr) in MELD score equation [[1]Myers R.P. Shaheen A.A. Aspinall A.I. Quinn R.R. Burak K.W. Gender, renal function, and outcomes on the liver transplant waiting list: Assessment of revised MELD including estimated glomerular filtration rate.J Hepatol. 2011; 54: 462-470Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. This confirms our previously published work indicating a systematic bias against women [[2]Cholongitas E. Marelli L. Kerry A. Goodier D.W. Nair D. Thomas M. et al.Female liver transplant recipients with the same GFR as male recipients have lower MELD scores – a systematic bias.Am J Transplant. 2007; 7: 685-692Crossref PubMed Scopus (125) Google Scholar]. It is known that Cr is an inaccurate marker of renal function, since its concentration is influenced by several factors unrelated to renal function, such as total muscle mass, leading to discrepancies in Cr concentration between individuals with the same renal function [same glomerular filtration rate (GFR)] but of different age, race and sex [[3]Cholongitas E. Shusang V. Marelli L. Nair D. Thomas M. Patch D. et al.Review article: renal function assessment in cirrhosis – difficulties and alternative measurements.Aliment Pharmacol Ther. 2007; 26: 969-978Crossref PubMed Scopus (127) Google Scholar]. We showed that Cr and GFR in females were lower than males, and female gender might negatively influence the chances of receiving a liver transplant with respect to men [[2]Cholongitas E. Marelli L. Kerry A. Goodier D.W. Nair D. Thomas M. et al.Female liver transplant recipients with the same GFR as male recipients have lower MELD scores – a systematic bias.Am J Transplant. 2007; 7: 685-692Crossref PubMed Scopus (125) Google Scholar]. Correcting Cr by equalising the GFR between men and women, resulted in an increase in MELD score by up to 3 points in female LT candidates [[2]Cholongitas E. Marelli L. Kerry A. Goodier D.W. Nair D. Thomas M. et al.Female liver transplant recipients with the same GFR as male recipients have lower MELD scores – a systematic bias.Am J Transplant. 2007; 7: 685-692Crossref PubMed Scopus (125) Google Scholar]. Following this, Moylan et al. evaluated the UNOS database [[4]Moylan C.A. Brady C.W. Johnson J.L. Smith A.D. Tuttle-Newhall J.E. Muir A.J. Disparities in liver transplantation before and after introduction of the MELD score.JAMA. 2008; 300: 2371-2378Crossref PubMed Scopus (266) Google Scholar] and showed that women were more likely to die on the waiting list in the post-MELD era, compared to the pre-MELD one, although women were listed with lower median MELD scores, compared to men (14 vs. 15, p <0.001) [[4]Moylan C.A. Brady C.W. Johnson J.L. Smith A.D. Tuttle-Newhall J.E. Muir A.J. Disparities in liver transplantation before and after introduction of the MELD score.JAMA. 2008; 300: 2371-2378Crossref PubMed Scopus (266) Google Scholar]. In the UNOS database, Myers et al. [[1]Myers R.P. Shaheen A.A. Aspinall A.I. Quinn R.R. Burak K.W. Gender, renal function, and outcomes on the liver transplant waiting list: Assessment of revised MELD including estimated glomerular filtration rate.J Hepatol. 2011; 54: 462-470Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar] found the same discrepancies, as we did [[2]Cholongitas E. Marelli L. Kerry A. Goodier D.W. Nair D. Thomas M. et al.Female liver transplant recipients with the same GFR as male recipients have lower MELD scores – a systematic bias.Am J Transplant. 2007; 7: 685-692Crossref PubMed Scopus (125) Google Scholar]: women, compared with men, had lower Cr (0.9 vs. 1.0 mg/dl, and MELD 16.5 vs. 17.2, both p <0.001), but worse renal function (estimated GFR: 72 vs. 83 mL/min, p <0.001); however they were less likely to undergo liver transplantation (LT), and had greater 3-month mortality. Interestingly, Myers et al. [[1]Myers R.P. Shaheen A.A. Aspinall A.I. Quinn R.R. Burak K.W. Gender, renal function, and outcomes on the liver transplant waiting list: Assessment of revised MELD including estimated glomerular filtration rate.J Hepatol. 2011; 54: 462-470Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar] also found that patients with cirrhosis with a black ethnicity had a lower mortality, compared to white ethnicity. We believe that this likely to be related to Cr: black patients as a group have a higher Cr (more muscle mass), compared to white, for the same renal function, and, thus, MELD score may overestimate the severity of their liver disease. Indeed, MDRD calculations of GFR commonly have a correction factor for black race. However Myers et al. did not find that using a calculated GFR (eGFR based on MDRD formula) helped to discriminate a different prognosis for men vs. women [[1]Myers R.P. Shaheen A.A. Aspinall A.I. Quinn R.R. Burak K.W. Gender, renal function, and outcomes on the liver transplant waiting list: Assessment of revised MELD including estimated glomerular filtration rate.J Hepatol. 2011; 54: 462-470Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. However, the evaluation with eGFR (MDRD formula), and not with “true” GFR using a gold standard method, could explain the discrepant results regarding the comparison presented of MELD-(Sodium)-eGFR and MELD-(Sodium) as the authors themselves suggested [[1]Myers R.P. Shaheen A.A. Aspinall A.I. Quinn R.R. Burak K.W. Gender, renal function, and outcomes on the liver transplant waiting list: Assessment of revised MELD including estimated glomerular filtration rate.J Hepatol. 2011; 54: 462-470Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. In contrast, Lim et al. [[5]Lim Y. Larson T. Benson J. Kamath P. Kremers W. Therneau T. et al.Serum sodium, renal function and survival of patients with end-stage liver disease.J Hepatol. 2010; 52: 523-528Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar] (using 125I-iothalamate for true GFR) found that “true” GFR was superior to Cr in assessing mortality risk on the waiting list and its incorporation in the MELD score (in the place of Cr), led to a significant improvement of discriminative ability of MELD. Unfortunately, Lim et al. [[5]Lim Y. Larson T. Benson J. Kamath P. Kremers W. Therneau T. et al.Serum sodium, renal function and survival of patients with end-stage liver disease.J Hepatol. 2010; 52: 523-528Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar] did not evaluate the prognostic impact of MELD-Cr and MELD-GFR scores in men and women candidates separately. Secondly, it is possible that the higher mortality of women placed on waiting lists for liver transplantation [1Myers R.P. Shaheen A.A. Aspinall A.I. Quinn R.R. Burak K.W. Gender, renal function, and outcomes on the liver transplant waiting list: Assessment of revised MELD including estimated glomerular filtration rate.J Hepatol. 2011; 54: 462-470Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 4Moylan C.A. Brady C.W. Johnson J.L. Smith A.D. Tuttle-Newhall J.E. Muir A.J. Disparities in liver transplantation before and after introduction of the MELD score.JAMA. 2008; 300: 2371-2378Crossref PubMed Scopus (266) Google Scholar], compared to men, could be related to the presence of significant differences for matching of donor organ size to either recipient men or women, and thus, longer waiting times for women compared to men. Unfortunately, Myers et al. [[1]Myers R.P. Shaheen A.A. Aspinall A.I. Quinn R.R. Burak K.W. Gender, renal function, and outcomes on the liver transplant waiting list: Assessment of revised MELD including estimated glomerular filtration rate.J Hepatol. 2011; 54: 462-470Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar] did not evaluate this parameter. However, Lai et al. [[6]Lai J.C. Terrault N.A. Vittinghoff E. Biggins S.W. Height contributes to the gender difference in wait-list mortality under the MELD-based liver allocation system.Am J Transplant. 2010; 10: 2658-2664Crossref PubMed Scopus (84) Google Scholar] recently suggested that height contributes to the gender disparity, possibly reflecting differences in transplantation rates for shorter individuals. The authors showed that short stature is related with higher risk of death for both men and women. Since women have shorter stature, compared to men, this could explain the higher waiting list mortality of women. However, data regarding the waiting time between men and women, or between different heights of candidates were not provided, and height cannot totally explain this disparity. Thus, as the authors recognized [[6]Lai J.C. Terrault N.A. Vittinghoff E. Biggins S.W. Height contributes to the gender difference in wait-list mortality under the MELD-based liver allocation system.Am J Transplant. 2010; 10: 2658-2664Crossref PubMed Scopus (84) Google Scholar], further investigation is needed to clarify the issue of gender disparity and organ allocation in liver transplantation. Nevertheless, it seems that female gender predicts lower transplantation rates, independently of height. A further recent study [[7]Mindikoglu A.L. Regev A. Seliger S.L. Magder L.S. Gender disparity in liver transplant waiting-list mortality: the importance of kidney function.Liver transpl. 2010; 16: 1147-1157Crossref PubMed Scopus (61) Google Scholar] again showed that women had lower transplantation rates and a substantially higher mortality risk on the LT waiting list, particularly when eGFR was between 15 and 30 ml/min, due to underestimation of renal dysfunction in women, when Cr was used for MELD score calculation. As we stated [[2]Cholongitas E. Marelli L. Kerry A. Goodier D.W. Nair D. Thomas M. et al.Female liver transplant recipients with the same GFR as male recipients have lower MELD scores – a systematic bias.Am J Transplant. 2007; 7: 685-692Crossref PubMed Scopus (125) Google Scholar], we believe that a correction factor for gender and ethnicity should be introduced for equitable allocation in liver transplantation particularly if a MELD based system is used. As “true” GFR is difficult to perform routinely, and new serum markers, such as cystatin C and its mathematical formulae, seem to offer no significant advantage, compared to Cr and the MDRD formula, in patients with cirrhosis [[8]Xirouchakis E. Marelli L. Cholongitas E. Manousou P. Calvaruso V. Pleguezuelo M. et al.Comparison of Cystatin C and Creatinine-based Glomerular Filtration Rate Formulas with 51Cr-EDTA Clearance in Patients with Cirrhosis.Clin J Am Soc Nephrol. 2011; 6: 84-92Crossref PubMed Scopus (56) Google Scholar], a different parameter is needed. Thus, a simple increase of points should be instituted for women awaiting LT when MELD is used, or indeed in other formulae that use Cr, as unequal access to transplantation between men and women has now been shown by several groups [1Myers R.P. Shaheen A.A. Aspinall A.I. Quinn R.R. Burak K.W. Gender, renal function, and outcomes on the liver transplant waiting list: Assessment of revised MELD including estimated glomerular filtration rate.J Hepatol. 2011; 54: 462-470Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 4Moylan C.A. Brady C.W. Johnson J.L. Smith A.D. Tuttle-Newhall J.E. Muir A.J. Disparities in liver transplantation before and after introduction of the MELD score.JAMA. 2008; 300: 2371-2378Crossref PubMed Scopus (266) Google Scholar, 6Lai J.C. Terrault N.A. Vittinghoff E. Biggins S.W. Height contributes to the gender difference in wait-list mortality under the MELD-based liver allocation system.Am J Transplant. 2010; 10: 2658-2664Crossref PubMed Scopus (84) Google Scholar, 7Mindikoglu A.L. Regev A. Seliger S.L. Magder L.S. Gender disparity in liver transplant waiting-list mortality: the importance of kidney function.Liver transpl. 2010; 16: 1147-1157Crossref PubMed Scopus (61) Google Scholar] following our first report [[2]Cholongitas E. Marelli L. Kerry A. Goodier D.W. Nair D. Thomas M. et al.Female liver transplant recipients with the same GFR as male recipients have lower MELD scores – a systematic bias.Am J Transplant. 2007; 7: 685-692Crossref PubMed Scopus (125) Google Scholar]. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.