Original Clinical Science—Liver

Center-related Bias in MELD Scores Within

a Liver Transplant UNOS Region: A Call for
Standardization
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Elizabeth C. Verna, MD, MS,1 Charles Connelly,2 Lorna M. Dove, MD, MPH,1 Patricia Adem, MD,3
Nikolina Babic, PhD,4 James Corsetti, MD, PhD,5 James Faix, MD,6 Joshua A. Hayden, PhD,7
Mark Lifshitz, MD,8 Brie Stotler,2 Zhezhen Jin, PhD,9 Sumit Mohan, MD, MPH,10,11 Jean C. Emond, MD,1
Eldad A. Hod, MD,2 and Alexander Kratz, MD, PhD2

Background. Model for End-Stage Liver Disease (MELD) score–based liver transplant allocation was implemented as
a fair and objective measure to prioritize patients based upon disease severity. Accuracy and reproducibility of MELD is
an essential assumption to ensure fairness in organ access. We hypothesized that variability in laboratory methodology
between centers could impact allocation scores for individuals on the transplant waiting list. Methods. Aliquots of 30
patient serum samples were analyzed for creatinine, bilirubin, and sodium in all transplant centers within United Network
for Organ Sharing (UNOS) region 9. Descriptive statistics, intraclass correlation coefficients (ICCs), and linear mixed-effects
regression were used to determine the relationship between center, bilirubin, and calculated MELD-sodium (MELD-Na)
score. Results. The mean MELD-Na score per sample ranged from 14 to 38. The mean range in MELD-Na per sample
was 3 points, but 30% of samples had a range of 4–6 points. Correlation plots and intraclass correlation coefficient analy-
sis confirmed bilirubin interfered with creatinine, with worsening agreement in creatinine at high bilirubin levels. Center and
bilirubin were independently associated with creatinine reported in mixed-effects models. Unbiased hierarchical clustering
suggested that samples from specific centers have consistently higher creatinine and MELD-Na values. Conclusions.
Despite implementation of creatinine standardization, centers within a single UNOS region report clinically significant dif-
ferences in MELD-Na on an identical sample, with differences of up to 6 points in high MELD-Na patients. The bias in
MELD-Na scores based upon center choice within a region should be addressed in the current efforts to eliminate dispari-
ties in liver transplant access.
(Transplantation 2020;104: 1396–1402).

Received 1 March 2019. Revision received 27 June 2019.

E.C.V. participated in research design, writing of the paper, performance of the
Accepted 6 August 2019. research, and data analysis. C.C. participated in research design, writing of
1
Center for Liver Disease and Transplantation, Columbia University, Vagelos the paper, performance of the research, and data analysis. L.M.D. participated
College of Physicians and Surgeons, New York, NY. in research design, writing of the paper, performance of the research, and
2 data analysis. P.A. participated in writing of the paper and performance of
Department of Pathology and Cell Biology, Vagelos College of Physicians and
the research. N.B. participated in writing of the paper and performance of
Surgeons, Columbia University, NewYork-Presbyterian Hospital, New York, NY.
the research. J.C. participated in writing of the paper and performance of
3
Department of Pathology, New York Medical College School of Medicine, the research. J.M. participated in writing of the paper and performance of
Valhalla, NY. the research. J.A.H. participated in writing of the paper and performance of
4
Department of Pathology, Mount Sinai Hospital, New York, NY. the research. M.L. participated in writing of the paper and performance of
5 the research. B.S. participated in writing of the paper and performance of
Department of Pathology and Laboratory Medicine, University of Rochester
the research. Z.J. participated in writing of the paper and data analysis. S.M.
Medical Center, Rochester, NY.
participated in research design, writing of the paper, performance of the
6
Department of Pathology, Montefiore Medical Center, Bronx, NY. research, and data analysis. J.C.E. participated in research design, writing of
7
Department of Pathology and Laboratory Medicine, Weill Cornell Medical the paper, performance of the research, and data analysis. E.A.H. participated
College, New York, NY. in research design, writing of the paper, performance of the research, and data
8 analysis. A.K. participated in research design, writing of the paper, performance
Department of Pathology, New York University Langone Health, New York, NY.
of the research, and data analysis.
9
Department of Biostatistics, Mailman School of Public Health, Columbia
J.A.H. received honoraria and research support from Roche Diagnostics. The
University, New York, NY.
other authors declare no conflicts of interest.
10
Department of Medicine, Division of Nephrology, Vagelos College of
Correspondence: Elizabeth C. Verna, MD, MS, Division of Digestive and Liver
Physicians and Surgeons, Columbia University, New York, NY.
Diseases, Columbia University College of Physicians and Surgeons. (ev77@
11
Department of Epidemiology, Mailman School of Public Health, Columbia columbia.edu).
University, New York, NY.
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Supplemental digital content (SDC) is available for this article. Direct URL
citations appear in the printed text, and links to the digital files are provided in the ISSN: 0041-1337/20/1047-1396
HTML text of this article on the journal’s Web site (www.transplantjournal.com). DOI: 10.1097/TP.0000000000003031

1396 Transplantation ■ July 2020 ■ Volume 104 ■ Number 7 www.transplantjournal.com

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<zdoi;10.1097/TP.0000000000003031>
 © 2019 Wolters Kluwer
INTRODUCTION
Since the inception of solid organ transplantation as a
life-saving treatment for organ failure, there has been sig-
nificant mismatch in organ supply and demand. Given the
scarcity of donor organs, fundamental debates regarding
the equity and utility of the transplant waitlist prioritiza-
tion system have persisted. The Model for End-Stage Liver
Disease (MELD) score was adopted for waitlist prioritiza-
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tion in the United States in 2002 and is seen as an objective
laboratory-based measure of liver disease severity due to
its ability to predict 90-day mortality without a transplant.
The MELD score initially incorporated serum creatinine,
bilirubin, and international normalized ratio (INR), with
high scores reflecting high mortality risk. Implementation
of the MELD-based transplant allocation system led to
decreased pretransplant mortality and improved trans-
plant rates without a decline in posttransplant survival1—
representing a significant improvement over the previous
largely time-based system.
While the MELD system continues to evolve to further
optimize the predictive power of the assigned score, the
system is plagued by significant geographic variation in
the median MELD scores at transplant across the United
States. As a result, geographic location has an unintended
impact on the level of illness (reflected by MELD) at which
patients can receive a life-saving transplant. The difference
in median MELD at transplant varied between regions by
as much as 12 points (35 versus 23) in 2015, the equiva-
lent of a 60% difference in the estimated risk of 3-month
mortality.2 Attempts at reducing this disparity in MELD at
transplant require changes in organ distribution that have
been the subject of intense debate in the liver transplant
community. However, using MELD parity as a goal of allo-
cation system changes requires that the MELD score itself
can be measured both accurately and reproducibly across
regions and transplant centers.
Unfortunately, variations in the creatinine and INR val-
ues obtained by using different laboratory methodologies
may significantly impact the calculated MELD score for a
given blood sample.3-6 Since these initial reports, nation-
wide standardization of creatinine measurements to isotope
dilution mass spectrometry (IDMS) has been implemented
to reduce interlaboratory variation.7 However, national
standardization and national proficiency laboratory test-
ing is limited to measurements in the absence of substances
that interfere with the assay. As bilirubin interferes with
the measurement of creatinine, and different laboratory
platforms are impacted by this interference to different
degrees, the benefit of IDMS standards is reduced in sam-
ples with high bilirubin concentrations. In addition, the
MELD score calculation has also become more complex
with the addition of sodium to the MELD (MELD-Na)
score in 2016, after demonstration that MELD-Na bet-
ter predicts waitlist mortality.8 How these changes have
impacted variability in measured MELD-Na, and how
center-based variability in measured MELD-Na impacts
the probability of transplant for patients at centers directly
competing for organs within a single United Network for
Organ Sharing (UNOS) region are not known.
We therefore determined the extent of variability in
MELD-Na score among the liver transplant centers within
a single UNOS region (region 9) with multiple transplant
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Verna et al 1397
programs. Furthermore, we sought to determine whether
there is bias placing specific patients or centers at a disad-
vantage for organ allocation resulting inadvertently from
an assay/platform choice of the hospital laboratory.
MATERIALS AND METHODS
Study Design and Procedures
Institutional review board approval was obtained from
Columbia University to allow for deidentification and test-
ing of residual patient blood specimens.
Thirty deidentified samples were selected to span the
analytical measurement range of total bilirubin (1–40 mg/
dL) and each sent to 8 laboratories at 7 participating liver
transplant centers within UNOS region 9. Samples were
pooled from multiple patient encounters to obtain a suf-
ficient volume. Aliquots (0.5 mL) were frozen and shipped
on dry ice to participating sites. Serum creatinine, total
bilirubin, and sodium were measured immediately upon
thawing at each site. INR cannot be measured in residual
serum samples and therefore could not be run. An INR of
1.5 was assigned for the MELD-Na calculation.
Sets of 2 frozen serum samples, with creatinine stand-
ardized to values of 0.847 ± 0.018 and 3.877 ± 0.082 mg/
dL by IDMS, were purchased from the National Institute
for Standards and Technology (NIST). To assess reproduc-
ibility, these NIST samples were tested multiple times at
each site until the sample was exhausted.
Participating Centers and Laboratory Equipment
Eight center-based laboratory sites at 7 liver transplant
centers in UNOS region 9 participated. Among the testing
sites, the following analyzer platforms were represented:
AU680 Chemistry System (Beckman Coulter Diagnostics,
Brea, CA), DxC 700 AU (Beckman Coulter Diagnostics),
Abbott Architect (Abbott Diagnostics, Abbott Park, IL),
Roche Cobas 6000 (Roche Diagnostics, Indianapolis, IL),
Roche Cobas 8000 (Roche Diagnostics), and Vitros 5600
(Ortho Clinical Diagnostics, Raritan, NJ). Depending on the
center, the kinetic alkaline picrate (Jaffe) or the enzymatic
method was used to measure creatinine. No 2 sites had the
identical combination of analyzer platform and creatinine
methodology. Both ion selective electrode and potentiomet-
ric methods for obtaining serum sodium were represented.
All sites used a Diazo method for measuring serum total
bilirubin. For the purposes of this report, the platform and
assay are deidentified to preserve the anonymity of the par-
ticipating centers (sites are labeled numbers 1–8, labora-
tory platform manufacturers are lettered A–D, and assay
methodology is indicated in subscripts 1–2). The creatinine
assay with the least interference by bilirubin was used as
the gold-standard test for the correlation plots.
Statistical Analyses
Descriptive statistics were performed using Prism
(GraphPad v5.0) and Stata 12.0 (College Station, TX).
Intraclass correlation coefficients (ICCs) were calculated
in Stata 12.0 using a 2-way mixed-effects model to assess
the agreement in the measurement of creatinine across the
8 participating sites that assessed each of the 30 samples.
In addition to assessing the ICC for sodium, bilirubin, and
creatinine, the ICC for creatinine was also assessed using
 1398 Transplantation ■ July 2020 ■ Volume 104 ■ Number 7
stepwise increase in the bilirubin threshold at which sam-
ples were included in the analysis.
A linear mixed-effects model was then utilized to evalu-
ate the impact of center, interfering substances (bilirubin),
the interaction between center and bilirubin on measured
creatinine using SAS v9.04 (SAS Institute Inc., Cary, NC).
Heatmaps and hierarchical clustering were performed
using R (v3.1.1; heatmap.2), using default Euclidean meas-
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tion method for clustering, to assess center-based bias in
measured creatinine and MELD-Na score.9
Finally, to evaluate the impact of changes in MELD-Na
score on access to transplantation, data from the Scientific
Registry of Transplant Recipients of adult liver transplant
candidates listed between June 2013 (when the Share 35
rule was implemented in organ allocation) and February
2017 were analyzed. The Share 35 policy was imple-
mented to further prioritize liver transplant candidates
with the highest risk of death without transplant (those
with MELD-Na scores ≥35) to receive offers from within
the entire UNOS region rather than only the local donor
service area. The proportion of patients transplanted
within 30 days of listing at each MELD-Na, nationally and
in region 9, was tabulated. Unadjusted logistic regression
was performed to estimate the odds ratio for transplant at
each MELD-Na score.
RESULTS
Reproducibility of Creatinine Measurements With
NIST Standards
The results of creatinine measurements using the NIST
standards are summarized in Figure S1 (SDC, http://links.
lww.com/TP/B838). For sample 1, mean results at the 8 sites
ranged from 0.795 to 0.896 mg/dL (coefficient of variability
= 1.8%). At 3 out of the 8 sites, all results were outside of
the allowable deviation. For sample 2, average results ranged
from 3.717 to 4.02 mg/dL (coefficient of variability = 1.0%).
For this sample, all results at 2 sites were out of the range
considered allowable by the NIST. Only 1 site (site 7) was
within the allowable range for both NIST samples on all tests.
Individual Assay and MELD-Na Variability Between
Sites
The overall ICC was moderate for creatinine (0.95; 95%
confidence interval, 0.90-0.98) and relatively weak for bili-
rubin (0.89; 0.83-0.94) and sodium (0.88; 0.81-0.94).
TABLE 1.
Summary of mean (range) assay results from the 8 laboratory sites
Site Creatinine (mg/dL) Total bilirubin (mg/dL)
1 2.0 (1.0–3.9)
2 2.2 (1.0–4.5)
3 2.01 (1.0–3.8)
4 2.0 (1.0–3.9)
5 1.8 (0.7–4.0)
6 2.1 (0.9–4.5)
7 2.1 (1.0–4.2)
8 2.2 (1.1–4.6)
Overall 2.1 (0.7–4.6)
MELD-Na, sodium to the Model for End-Stage Liver Disease.
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The overall mean creatinine for the samples was 2.1 mg/
dL (range: 0.7–4.6 mg/dL), with a mean measured creati-
nine from 0.99 to 3.95 mg/dL (Table 1). The overall mean
bilirubin for the samples was 13.9 mg/dL (range: 0.4–
47 mg/dL), with a mean measured bilirubin ranging from
1 to 40 mg/dL.
The mean calculated MELD-Na per sample ranged
from 14 to 39 (Figure 1, Table 1). The range in calculated
MELD-Na per sample (difference between the maximum
and minimum values) varied by 1–6 points, with an aver-
age of 3 MELD-Na points (Table 2). Overall, 30% of sam-
ples had a range of ≥4 MELD-Na points.
Impact of Center and Bilirubin on Creatinine
Measurements
As creatinine is heavily weighted in the MELD-Na
score, and there is a known impact of interfering sub-
stances including bilirubin on measured creatinine level,
additional analysis was performed specifically examin-
ing the impact of center and bilirubin level on creati-
nine results. Using results from a gold-standard test with
minimal bilirubin interference on creatinine levels, cor-
relation plots of bilirubin versus the percent difference in
creatinine level between the test and gold-standard result
for each sample are plotted to illustrate the bilirubin
interference on creatinine results (Figure 2). As bilirubin
values increased, creatinine values were biased lower for
some assay platforms.
The impact of rising bilirubin concentrations on esti-
mates of creatinine concentration was also demonstrable
by the decreasing ICC for creatinine across the sites as
the instances with lower bilirubin concentrations reported
were excluded (Figure 3A) such that for samples with a
bilirubin above 33, the ICC for creatinine had dropped
to 0.86.
Finally, the impact of center and bilirubin concentra-
tion on measured creatinine level was evaluated using
a multivariable linear mixed-effects model (Table 3).
In this model, center, bilirubin, and the interaction
between center and bilirubin were significantly predic-
tive of creatinine level. The magnitude of this effect was
dependent on the center’s choice in assay methodology
as shown by the parameter estimates for the interaction
term (bilirubin × center), with centers using assay plat-
form D (centers 3, 4, and 5) having the most significant
effect of bilirubin on creatinine measurements (Table 3
and Figure 2B).
Sodium (mmol/L) MELD-Na
11.8 (0.5–26.8) 134.9 (123–152) 26.8 (11.9–37.7)
13.07 (0.6–32.0) 139.2 (131–156) 26.1 (14.6–36.9)
13.6 (0.4–29.8) 137.7 (130–155) 26.7 (14.3–37.1)
13.6 (0.5–40.0) 139.2 (131–155) 26.2 (14.2–37.2)
14.2 (0.5–43.8) 137.7 (126–156) 25.9 (14.2–37.7)
14.7 (0.5–47.0) 137.3 (128–154) 27.1 (13.1–37.9)
14.5 (0.4–45.6) 137.6 (128–155) 27.1 (13.9–37.9)
14.9 (0.5–36.0) 137.3 (19–154) 27.9 (13.9–38.2)
13.9 (0.4–47.0) 137.6 (123–156) 26.9 (11.9–38.2)
 © 2019 Wolters Kluwer Verna et al 1399
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FIGURE 1. Distribution of sodium to the Model for End-Stage Liver Disease (MELD-Na) scores by individual sample.

TABLE 2.
Range in MELD-Na score per sample
Range MELD-Na score per sample Number (%)
1 4 (13)
2 9 (30)
3 8 (27)
4 3 (10)
5 4 (13)
6 2 (7)
MELD-Na, sodium to the Model for End-Stage Liver Disease.
Impact of Center on MELD-Na Score
As a result of the different relationships between biliru-
bin level and creatinine measurement interaction, there is
greater variability in MELD-Na score as bilirubin increases
(Figure 3B). The average range of MELD-Na scores was
2 for patients with the lowest bilirubin quartile (<7 mg/
dL) but 4 in patients with bilirubin in the highest quartile
(>20 mg/dL).
The impact of center on MELD-Na score is also dis-
played by unbiased hierarchical clustering of MELD-Na
scores and creatinine (Figure 4). Sites with identical plat-
forms and methods for obtaining creatinine levels, such as
3D1 and 4D1, clustered together. Site 5D2 used the same
platform but an alternative method, resulting in decluster-
ing from sites 3 and 4. In addition, it is clear from this
analysis that sites using platform A have the highest cre-
atinine values in almost all samples, with site 8 having the
highest MELD-Na score in 50% of cases.
Impact of MELD-Na Score on Access to Transplant
The differences in MELD-Na scores observed for
individual patient samples between centers may have a
substantial impact on access to transplant. A change in

FIGURE 2. Using results from a gold-standard test with minimal bilirubin interference on creatinine levels, correlation plots of bilirubin vs
the percent difference in creatinine level between the gold-standard and test result for each sample are plotted to illustrate the effect of
total bilirubin interference on creatinine. The number coding for each site in the legend represents the anonymized performing laboratory
(1–8), the letter (A–E) represents the instrument platform the laboratory utilized to obtain the results, and the subscript (1–2) represents
the methodology used to perform creatinine. The Pearson R2 and P are provided. A, Two sites using different analyzer platforms (1C and
2B) for performing creatinine with different relationships between bilirubin and percent difference in creatinine. B, Three sites all using the
same platform (D) with site 5D2 using a different assay and exhibiting a more substantial effect of bilirubin on creatinine measurements.

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 1400 Transplantation ■ July 2020 ■ Volume 104 ■ Number 7 www.transplantjournal.com

MELD-Na of 3–6 points for an individual patient leads to

significant differences in the 30-day probability of trans-
plant, both nationally and within region 9 (Table S1, SDC,
http://links.lww.com/TP/B838). For samples with extreme
ranges of up to 6 MELD-Na points, the impact may be
profound. For example, for the sample with a range in
calculated MELD-Na scores from 26 to 32, this amounts
to an approximately 50% difference in the probability
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of transplant in the subsequent 30 days, both nationally

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(25.5% versus 48.3%) and in region 9 specifically (41.2%

versus 83.3%). In addition, even small 1–2 point changes
in MELD-Na may have a significant impact, especially
around an allocation threshold such as MELD-Na of 35.
For example, as the Share 35 allocation policy that man-
dates regional sharing for all patients with MELD-Na of
≥35, a difference between MELD-Na of 33 and 35 results
in a 10% increase in probability of transplant within 30
days, again both regionally (49.0% versus 59.9%) and
nationally (75.0% versus 85.7%).

DISCUSSION
In this study, we identified highly significant differences
in MELD-Na allocation ranking due to the variation in
laboratory methodology between centers. This effect was
most pronounced at the highest scores, resulting in highly
significant differences in expected organ access between
individuals with the same actual severity of liver disease
in a given zone of distribution. This finding is concerning
because MELD-Na–based liver transplant allocation was
instituted to eliminate subjective clinical criteria from the
rank order on the waitlist.
FIGURE 3. Impact of bilirubin on creatinine variability. A, Intraclass
correlation coefficients (ICCs) for creatinine by increasing bilirubin In recent years, the literature has been replete with
level. B, Boxplots of range in calculated sodium to the Model studies concerning disparities in access to transplanta-
for End-Stage Liver Disease (MELD-Na) scores per sample by tion driven by factors other than liver disease severity. All
bilirubin quartile displaying the increased variability in MELD-Na of these studies have focused on the effects of geography
as bilirubin rises.
on access to transplantation, and the bias in distribution
based on geography. In March 2000, the US Department
of Health and Human Services promulgated the Final
TABLE 3. Rule, which instructs that allocation policies shall not be
Mixed-effects model to predict measured creatinine level based on the candidate’s place of residence or place of list-
ing except to the extent needed to satisfy other regulatory
Predictor Coefficient SE P requirements. Our work suggests that without standardi-
Center zation of MELD-Na determination, the second pillar of
1 −0.140 0.040 <0.001 the final rule, distribution in decreasing order of medical
2 0.072 0.041 0.08 urgency, is not being met either. While eliminating geo-
3 0.081 0.040 0.04 graphic disparities in MELD-Na at transplant has been the
4 −0.005 0.040 0.90 focus of current efforts to improve fairness, center-based
5 0.003 0.042 0.94 variability in laboratory platform and assay may create
6 −0.094 0.039 0.02 additional variability and bias within and between regions
7 −0.056 0.040 0.16 that should be considered in the current allocation debate.
8 Ref – – Within 8 laboratories in UNOS region 9, the mean
Total bilirubin 0.016 0.002 <0.001 range in calculated MELD-Na within single patient sam-
Total bilirubin × Center ples was 3 MELD-Na points, with one-third of samples
1 −0.006 0.002 0.01
with a range of 4 or more points. This variability spanned
the range in MELD scores from 14 to 39 but was the most
2 −0.006 0.003 0.02
pronounced in samples with high total bilirubin levels.
3 −0.021 0.002 <0.001
Almost a third of patients had a 4–6 point difference in
4 −0.016 0.002 <0.001
MELD-Na score, translating into an up to 50% change
5 −0.029 0.002 <0.001
in the probability of being transplanted in the subsequent
6 −0.004 0.002 0.08
30 days. Scores that straddle thresholds for changes in
7 −0.011 0.002 <0.001
sharing of organs, at both the high (MELD-Na >35) and
8 Ref – – low ranges (MELD-Na <15), could lead to dramatically

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 © 2019 Wolters Kluwer Verna et al 1401
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FIGURE 4. Center-based bias in MELDNa, creatinine and total bilirubin. Heatmaps illustrating unbiased hierarchical clustering of (A)
sodium to the Model for End-Stage Liver Disease (MELD-Na) scores, (B) creatinine at the participating sites, and (C) total bilirubin level.
Rows are ordered from lowest to highest mean bilirubin value. Green cells represent measured values with positive deviation from the
mean for the sample, while red represents a negative deviation. The number at the base of each column represents an anonymized
performing laboratory (1–8) and the letter (A–E) represents the instrument platform the laboratory utilized to obtain the results. The
subscript number represents the testing methodology used for creatinine on a given platform. The blue line running down each column
is a representation of the z score; deviations of this line represent movement away from the mean.

different access to transplant based upon laboratory tech-
nique rather than upon the inherent risk of poor outcomes.
While some variability in assay performance has been
previously reported and is perhaps expected, this is the first
report in which significant bias is demonstrated between
centers within a UNOS region. The center where the serum
was assayed was significantly predictive of measured cre-
atinine level and calculated MELD-Na. Thus, individual
patients may be given additional priority on the transplant
waiting list based upon their center or laboratory facility
rather than based upon their inherent risk of death with-
out transplant. As each of the MELD-Na components are
also accounted for in the Scientific Registry of Transplant
Recipients risk adjustment model that is utilized to assess
center performance, it is also possible that centers may be
inappropriately advantaged or disadvantaged on a regula-
tory basis when the laboratory measurements do not cor-
rectly reflect severity of disease.
Creatinine measurement is clearly impacted by labo-
ratory platform and assay methodology as well as the
presence of interfering substances, including bilirubin.10
Bilirubin is a chromogen that causes a negative interfer-
ence with creatinine measurements, usually resulting in
lower creatinine values. Several methods have been devel-
oped to overcome this interference, leading to different
results depending upon the assay utilized.11,12 The impact
of creatinine assay variability on calculated MELD has
also been explored in European studies, where significant
variation in measured creatinine across assay techniques
was documented, with increasing variability in patients
with high bilirubin levels and MELD scores.13,14
The national initiative to standardize creatinine meas-
urements to NIST standards should have reduced the
variability of MELD-Na scores. However, despite com-
pliance with this standardization protocol, many of the
sites measured values outside expected values when test-
ing NIST standards. In addition, these standards were not
created with interfering substances such as bilirubin pre-
sent in the sample. There is clearly a complex relationship
between the creatinine assay, the platform manufacturer,
and the interference of bilirubin on creatinine measure-
ment such that simply requiring a specific creatinine assay
may not completely eliminate this center-based effect.
Previous studies have also revealed that INR is a source of
variability in calculated MELD score.3,4 INR was not tested
in this present study as it cannot be run on residual serum
samples. This is a limitation of the current analysis as varia-
tion in INR between methodologies is significant, again with
the highest variation in the high MELD patients. Given the
differing methodologies between the laboratories in region
9, this would likely have further increased the variability
in calculated MELD-Na. In addition, we acknowledge that
many outpatients on the waiting list get laboratories done
at multiple laboratory facilities, often outside of their trans-
plant center. We did not send samples to these additional
facilities, but this may add additional variability.
Despite standardization efforts for creatinine and INR
reporting, these assays continue to perform poorly among
patients with cirrhosis, and UNOS has never performed a
widespread quality control study to understand the impact
of this variability on allocation. How to best address this
center-based disparity is not straightforward. Any proposal
for standardization must consider the logistical complexity of
thousands of patients having testing performed at hundreds
or thousands of transplant centers and local laboratories on
a regular basis. Mandating uniform methodology for all 4
measures in the MELD-Na score or centralized testing in a
UNOS region or donor service area is also likely not feasible.
In this era of greater accountability and federal report-
ing of laboratory-based measures, there is precedent for

Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 1402 Transplantation ■ July 2020 ■ Volume 104 ■ Number 7
adjusting for variability due to laboratory methodol-
ogy. Reporting of serum albumin for patients on dialysis
includes information on the method used15,16 to allow for
conversion of results to a common standard.17 However,
to accurately determine the level of adjustment needed for
each measure will require further studies. Finally, it has
also been proposed that standards with interfering sub-
stances also be used to calibrate laboratory equipment,
Downloaded from http://journals.lww.com/transplantjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4
perhaps at least at transplant centers and private laborato-
XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 02/28/2024
ries seeking certification for MELD-Na testing. It is clear
that UNOS and the transplant community would benefit
from a more comprehensive investigation into the under-
recognized impact of laboratory test variability on organ
allocation and clinical outcomes on both the center and
individual level. The extent to which providers and pro-
grams are already directing patients to facilities known to
produce higher MELD scores is unknown. It is also pos-
sible that for patients with significant cholestasis, such as
those with severe alcohol-related hepatitis, there will be
more significant variability between laboratories.
In the United States, access to donated organs is
affected by 2 independent aspects: distribution, the geo-
graphic zone defining the recipient population within
which the organ is primarily offered, and allocation, the
rank order with which the offer is made which is based
on disease severity defined by MELD-Na. We have dem-
onstrated a clinically relevant interlaboratory variation
in calculated MELD-Na score among the transplant
centers directly competing for organs in UNOS region 9.
This variability was in part driven by creatinine, which
was independently predicted by the center where it was
assayed. These differences led to consistently higher or
lower creatinine and MELD-Na values at individual cent-
ers, impacting organ access in a nonrandom fashion. This
suggests a troubling scenario in which a patient could
change their position on the list by selecting a laboratory
with assays that consistently report higher creatinines,
undermining the principles of fair allocation based upon
an objective measure of liver function. This bias should
be considered in current efforts to eliminate disparities in
liver transplant access.
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