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Accepted for publication in The Lancet on 30th of August 2016. Ref: THELANCET-D-16-01100R2

Title PagePost-listing survival for highly sensitised patients on the UK kidney transplant waiting list, a matched cohort analysis

Authors: Manook M1, Koeser L2, Ahmed Z1, Robb M3, Johnson R3, Shaw O1, Kessaris N1, Dorling A1,4, Mamode N1

Department & Institution: 1. Department of Transplantation, Guy’s and St Thomas’ NHS Foundation Trust, 2. King’s Health Economics, Health Services and Population Research Department,

Institute of Psychiatry, Psychology and Neuroscience at King’s College, London3. NHS Blood & Transplant, Bristol, UK4. MRC Centre for Transplantation, King’s College London, Guy’s Hospital

Corresponding author:Professor Nizam MamodeDepartment of Transplantation6th Floor, Borough WingGreat Maze Pond, London, EnglandSE1 9RTTelephone: +44 (0)20 7188 1543Fax: + 44 (0)20 7188 5646Email: [email protected]

Running Title:Post-listing survival for highly sensitised patients on the UK kidney transplant waiting list

Key words:HLA-incompatible, Living Donor Renal Transplant, Highly Sensitised, Antibody incompatible transplantation, Survival.

Abbreviations:

ABOi ABO antibody incompatibleCDC Complement Dependent CytotoxicitycDD Compatible Deceased DonorcLD Compatible Living DonorDBD Donation after brainstem death

1

mailto:[email protected]

DCD Donation after circulatory deathDD Deceased Donor recipientDSA Donor Specific AntibodyFXCM Flowcytometric cross matchHLAi Human Leukocyte Antigen- incompatibleLD Living donorKPD Kidney Paired DonationUKLKDSS UK Living kidney donor sharing scheme

2

Abstract

Background: Over 40% of patients awaiting a kidney transplant in the UK are sensitised with HLA antibodies. Median time to transplantation for such patients is double that of unsensitised patients. Removing antibody to perform an HLA-incompatible (HLAi) living donor transplantation is perceived to be high risk, however, patient survival data is limited. We compared survival of patients opting for an HLAi kidney transplant to that of similarly sensitised patients awaiting a compatible organ.

Methods: From the UK adult kidney transplant waiting list, we selected crossmatch positive living donor HLAi kidney transplant recipients who received their transplant between 1.1.2007 and 31.12.2013, and were followed up to 31.12.2014 (end of study), along with a matched cohort of similarly sensitised patients listed for a deceased-donor transplant during that period. Data was censored both at the time of transplant (‘Listed only’), and at the end of the study period (‘Listed or Transplant’). We used Kaplan-Meier curves to compare patient survival between HLAi and the matched cohort.

Findings: Of 25,518 patient listings, 213 underwent an HLAi transplant during the study period. 852 (4 to 1) matched controls were identified. Of those, 41% remained untransplanted at just under 5 years after matching. There was no statistically significant difference in patient survival between ‘HLAi’ and either ‘Listed only’ (log rank, p = 0·446), or ‘Listed or Transplant’ (log rank, p = 0·984).

Interpretation: Survival of sensitised patients undergoing HLAi in the UK is comparable to those on dialysis awaiting a compatible organ, many of whom are unlikely to be transplanted. Choosing a direct HLAi transplant has no detrimental impact on survival, but conversely offers no survival benefit, in contrast to similar patients studied in a North American multicenter cohort.”

Funding: UK National Health Service Blood & Transplant, and Guy’s & St Thomas’ National Institute for Health Research Biomedical Research Centre.

3

Introduction

For many patients with end-stage renal disease (ESRD) awaiting a kidney transplant,

sensitization to Human Leukocyte Antigens (HLA) by blood transfusion, pregnancy or

previous transplantation, resulting in circulating antibodies (HLA-antibody), adversely

affects the chances of obtaining a suitable donor organ. In the UK, the level of sensitization

is estimated by the calculated reaction frequency (cRF), which estimates the percentage of

deceased donors against whom the recipient has preformed anti-HLA antibodies. Over a

quarter (26%) of patients on the waiting list are ‘highly sensitised’, with a cRF ≥85%; for

these patients transplant waiting time is doubled to a median of 6 years, compared to

patients with a cRF <10% (1).

Living donor kidney transplantation (LDKT) is the preferred treatment for ESRD, but for

many sensitised patients, this is impossible because anti-donor HLA antibodies result in a

positive crossmatch against their donor. This test indicates a very high risk of immediate

rejection(2) and therefore precludes transplantation, unless the patients undergo

antibody-removal (or ‘desensitisation’). There are five transplant possibilities currently

available for such patients: direct HLA-incompatible (HLAi) living donor kidney

transplantation following desensitisation; crossmatch negative (i.e.’compatible’) living

donor transplantation via the UK Living Donor Kidney Sharing Scheme (UKLDKSS); a

combination of both UKLDKSS and HLAi-transplantation; finding an alternative compatible

living donor, or awaiting a compatible deceased donor kidney.

In principle, the UKLDKSS offers a good opportunity for such patients to obtain a

compatible living donor transplant through a kidney paired donation (KPD) scheme. In

reality, the number of highly sensitised patients transplanted remains small (3). In 2014-

2015, for example, 66% of patients registered in the paired scheme had a cRF of >85%.

However, between 2012-2015, only 33% (n = 67) of UKLDKSS transplants were

undertaken in patients with a cRF >85%. Patients with a cRF of >95% have consistently

been found to make up 50% of the pool in each matching run (unpublished data, NHSBT).

Direct HLAi transplantation requires desensitization prior to transplantation (usually with

a combination of plasmapheresis and IVIg, to achieve a negative crossmatch) and enhanced

immunosuppression for induction and maintenance. This type of intensive regimen is not

4

suitable for patients with significant co-morbidities (4-7). In the UK, direct HLAi is not

currently offered by all centres.

For patients where direct HLAi transplantation is not feasible, either because of co-

morbidities or because the level of donor specific antibody (DSA) is too high to reduce, and

paired donation has not been successful, a combination of UKLDKSS and HLAi can be

used(8, 9), where desensitization allows a feasible HLAi transplant within the sharing

scheme. Unfortunately, for many sensitised patients these options are either not available

or acceptable, and the only other transplant options are to find alternative compatible

living donors, or wait for a compatible deceased donor kidney (10, 11); the wait may be

long or indefinite.

A key consideration for transplantable sensitised patients, is the likelihood of survival after

HLAi transplant. Desensitisation treatment itself confers increased risk of morbidity,

and HLAi results in an increased mortality and morbidity when compared with compatible

transplantation (12). In the USA, HLAi has been demonstrated to be more cost-effective

than dialysis (13).

Although this kind of data is useful for those patients who have a compatible donor, the

practical question for most patients and transplant doctors is whether to go ahead with a

direct HLAi transplant or wait on dialysis for one of the described alternatives, which might

never materialise. Multicentre data from the USA suggests that there is a survival benefit in

having an HLA-incompatible transplant, compared to waiting on dialysis for a compatible

alternative (14). However given the difference in dialysis mortality between USA and

Europe(15, 16), this may not hold true in the UK. Therefore, we used a national multicentre

assessment of survival outcome to answer the question, ‘Is the survival of highly sensitised

patients in the UK, following a direct HLAi transplant requiring desensitization, different to

patients who wait for a compatible alternative from the deceased donor list or through the

KPD scheme?’ In addition, for those patients choosing to await a compatible transplant, we

wanted to characterize how many patients were transplanted, and compare graft survival

between comparable patients receiving HLAi compared to compatible alternatives.

5

Methods

Study population

Patients were selected from the UK Adult renal transplant waiting list database for this

matched case control study. Managed by NHS Blood & Transplant (NHSBT), it contains

mandatory listing data used for renal transplant allocation. Information relating to

registration in the UKLDKSS was also linked using the registration ID. Data was extracted

relating to all patients on the waiting list on 1.1.2007, and all subsequently listed patients

until 31.12.2013, with follow up data to 31.12.2014 (n = 25,518).

The treatment group of interest were HLAi recipients of living donor renal transplants

from the UK renal transplant waiting list with a positive cross match after 1.1.2007. A

positive cross match was defined either by flow cross matching, (FXCM), or complement

dependent cytotoxicity (CDC), and was reported by local laboratories to the central

database. Although some centres in the UK classify cross-match negative recipients with a

DSA identified by Luminex testing as HLAi transplants, this is not consistent so these

patients are not included in this analysis. The controls were selected from patients listed

after 1.1.2007 who did not receive an HLAi transplant.

Patients originally listed on the paediatric waiting list, ABO-incompatible recipients and

deceased donor HLAi recipients were excluded, as these factors might be expected to be

associated with a different degree of risk when compared to adult living donor HLAi.

The primary outcome measure was post-transplant survival for HLAi, and post-listing

survival for the control groups. Further, we provide a detailed description of transplant

outcomes for patients in the control group as well as graft survival in all transplant

recipients.

Matched Controls

Patients receiving an HLAi tend to have different characteristics compared to those

receiving other types of treatment. Therefore, we matched each of the HLAi recipients to

several controls using multivariate matching. Matching variables were selected on the basis

of initial univariate analyses, as well as evidence from previous studies(17). Specifically,

6

these were age, gender, cRF score, blood group (type 0 and type A), diabetes as primary

cause of ESRD, length of registration in paired scheme, number of previous transplants and

duration of end stage renal disease (ESRD). We defined the latter as time since first chronic

dialysis or first previous transplantation - whichever came earlier or 0 if the patient had

received neither a transplant nor dialysis treatment at the index date. Since 70% of patients

who received a transplant had the same cRF score at listing as at the day of transplant and

80% had a cRF score within ±10 of their listing score, we assumed that cRF was constant

over time for the purpose of matching.

We performed risk-set matching in an attempt to approximate what would have happened

to patients who were observed to have received an ‘HLAi’ transplant had they not received

this treatment (18).In other words, we determined the time t from the date of registration

on the waiting list that it took for each HLAi recipient to obtain a transplant and

constructed a custom pool of potential matches for each of these index cases. This pool

included patients who had not received another transplant or died within the same time

interval after wait listing but excluded patients for whom time t fell before 1.1.2007

because, by definition, our sample only contained patients who had not received a

transplant or died before this date. In the subsequent analysis we compared outcomes of

HLAi patients after the date of transplant, with that of matched controls from time t after

wait listing.

Based on recommendations by Ho et al., we did not assess the balance between the

treatment and the control group using statistical tests (19). Instead, we compared the mean

values, the distribution of continuous variables using quantile-quantile plots and

differences at the individual level for categorical and binary variables. Further

methodological details including a description of the three types of matching approaches

that we have used to test the robustness of our results can be found in the appendix

methods.

Statistical analysis

We performed two comparisons. In the first comparison we censored survival of the

matched controls at the day of transplant (‘Listed only’). In the second comparison, termed

7

‘Listed or Transplant’, we used the same matched control group but followed them until

31.12.2014 or death.

We used the Kaplan-Meier method, and the log-rank test to compare rates of patient

survival between the treatment group ‘HLAi’ and ‘Listed only’ and ‘Listed or Transplant’ as

well as the rate of graft survival between ‘HLAi’ and those matches who received a

compatible deceased donor (cDD) or a compatible living donor (cLD) at some point. As an

alternative and more readily interpretable summary measure of our primary outcome, we

also calculated the difference in restricted mean patient survival, that is, the difference in

average survival time between the groups at 3, 5 and 7 years (20). In this analysis we also

adjusted for any significant imbalances that remained between the groups after matching,

with ‘significant’ defined as a mean difference of more than one tenth of a standard

deviation. As indicated above, we performed these primary analyses using three different

matching approaches to assess the sensitivity of results. Given the known difficulties of

organ allocation and transplantation of patients with the highest cRFs (>85%) as described

earlier, we also conducted a subgroup analysis of patients with cRF of >85% using our base

case matching approach.

Since it is not possible to receive a cLD transplant in the same registry period after having

received a cDD transplant or vice versa, we used a competing risk framework to estimate

the cumulative incidence of transplant status in the matched controls (21), Figure 2. As

previously noted, membership in the KPD scheme is likely to alter the probability of

receiving a transplant. In addition, some residual imbalance in this respect remained after

matching due to the large difference in paired scheme status between HLAi’s and potential

matches (30% vs. 3% registered). Therefore, we reported both the transplant outcomes for

three categories of paired scheme status, i.e. unregistered matches, matches registered for

<12 months and matches registered for >12 months in the paired scheme at time t as well

as a weighted average of these based on the proportions of HLAi’s in each category at time

t.

We used Stata v14·1 and R v3·2·3 for our analyses.

Results

8

We obtained listings for 25,518 patients. Of the 478 patients registered as receiving HLAi

kidney transplants, 137 were excluded as they were from deceased donors, and 123 did not

have a positive cross match. Five patients were excluded from this group as they were

originally listed on the paediatric waiting list.

Therefore, the treatment group was 213 adult HLAi recipients of cross-match positive LD

kidneys, transplanted in the UK from 1.1.2007 until 31.12.2013. The mean age at the time

of transplant was 44yrs ± 11yrs. The majority were female (65·7%) with a median cRF of

96% (IQR 20). Over half (53·1%) of HLAi recipients had received a previous renal

transplant, 46·9% were blood group O, mean duration of ESRD was 7·9 years (IQR 14·6)

see Table 1.

From the remaining 25,040 listed patients, 801 were excluded as they were originally

listed on the paediatric waiting list; 370 received ABO-incompatible transplants and 16 had

gender data missing. See Fig. 1 for full inclusion and exclusion details.

Matched controls

Using the matching methods described for our base case analysis, we then identified 852

matched controls from the remaining 23,865 patients. The differences in average patient

characteristics between the HLAi treatment group and, the matched controls were

generally lower than one tenth of a standard deviations and the ratio of variances was

between 1 and 1 1 (see Table 1)(22). In addition, as reflected in Figures A1-A8 the

distribution of age, gender, blood group, cRF, time on dialysis, diabetes as cause of ESRD

and previous transplantation was comparable between HLAis and matched controls (see

Appendix). The only exception from this was that approximately 12% more patients in the

‘HLAi’ group were member of the paired scheme at the time of transplant.

Transplant status and UK Living Donor Sharing Scheme membership (UKLDKSS)

In the HLAi -treatment group, 31% had been registered in the UKLDKSS, of these five

patients received a transplant through the UKLDKSS which combined HLAi with KPD. In

the matched controls, 18·7% of patients were registered in the UKLDKSS at the time of

matching and 20·8% were ever registered in the UKLDKSS. Adjusting for imbalances in

paired scheme enrollment by reweighing the sample, and the competing risks of cLD and

9

cDD (see methods), at just under 5 years after the matching date approximately 41% of the

matched controls remained untransplanted, 39% had received a cDD and 20% a cLD

transplant.(Fig 2). Matches registered in the paired scheme for less than 12m received the

highest proportion (43%) of compatible LD (cLD) transplants within the 1st year of the

study; for those who were registered for over 1 year in the UKLDKSS, this was substantially

lower (12%), while for those unregistered in the paired scheme, the rate of cLD transplants

remained low and constant over the study period, Appendix Figure 9. The observed effect

of the success of the UKLDKSS in the first 12m after registration is reflected in the similar

likelihood of a cDD or a cLD in the matched cohort within the first year of the study,

however this is not sustained over time, Fig 2.

Graft survival for HLAi recipients compared to matched controls

Mean death-censored graft survival was consistently highest for cLD recipients, and lowest

for HLAi. At 1 year post transplant, graft survival rates were 88% for HLAi, 96% for cLD

and 92% for cDD. By 5 years graft survival was 68% for HLAi; 89% for cLD and 77% for

cDD. These differences were statistically significant with p=0.002 and p=0.046 for the log-

rank tests of HLAi graft survival compared to cLD and cDD respectively, Fig 3.

Patient survival for HLAi recipients compared to matched controls

Overall, there was no statistically significant difference in patient survival between those

receiving an HLAi transplant, and either ‘Listed or Transplant’ (Log rank, p = 0·984) or

‘Listed only’ (Log rank, p = 0·446). Comparing HLAi to 'Listed or Transplant', restricted

mean survival time was 0·2 months higher in the latter at 3 years (SD 0·4, 95% CI -0·6 to 1,

p=0 649); 0·1 months higher at 5 years (SD 0·8, 95%CI -1·5 to 1·8, p=0·893) and – 0·1

months lower at 7 years (SD 0·9, 95% CI -1·9 to 1·6, p=0·866), Fig 4 & Table 2. The

sensitivity analyses in the appendix and the subgroup analysis restricted only to patients

with a cRF of >85% support these findings, Fig 5 & Table 2, Appendix Figures 9-11.

Discussion

For patients receiving a cross match positive HLAi transplant in the UK, there is no patient

survival benefit compared to patients with the same degree of HLA sensitization who wait

for a compatible alternative organ from either the deceased donor list or through the KPD.

In comparison to the situation reported in the US (14), this equivalence is marked, and

10

appears to be due to the excellent dialysis survival outcomes for these highly sensitised

patients listed for an organ. Two other things are apparent. First, just under half (43%) of

patients who wait for a compatible organ are unlikely to be transplanted under 5 years

years after listing; secondly, our data confirms that immediate short-term graft survival of

HLAi transplants is acceptable, but in the longer term, graft survival is poorer than

compatible alternatives.

These data are suggestive of a more nuanced picture of risk and benefit to be presented by

clinicians to highly sensitised patients with an HLA incompatible living donor. Although an

HLAi incompatible transplant does not confer a survival benefit, it does represent a choice

of a timely transplant for patients who otherwise have a great deal of uncertainty with

respect to their future. In this model, supporting current UK practice, for patients with an

HLAi donor who have not yet registered in the paired scheme, the best of a chance of a

compatible living donor transplant through the UKLDKSS is within 12 months of

registration, while beyond this the rate of allocation plateaus (Appendix Figure 7).

There are some inevitable limitations in a retrospective study based on registry data. We

have defined HLAi as transplants that are cross match positive because of a donor specific

antibody (DSA). The definition of a positive cross match, when performed either by FXCM,

or CDC may vary by technique and local laboratory values. Clearly a centrally standardized

cross match would give further confidence regarding the definition of ‘HLAi’ status, but this

was not possible. Estimating the effect of this on our results is difficult, however, limiting

our analysis to only cross match positive ensures a consistency of immunological risk,

given how good outcomes are for patients who are positive for DSA but have a negative

FXCM (12).

We have used diabetes as the primary cause of ESRD as a matching variable, however it

should be noted that although co-morbidity data relating to diabetes would have been

highly desirable, this data is not routinely collected by NHSBT.

Most transplant units in the UK recommend that patients with an HLAi living donor spend a

period of time in the UKLDKSS before considering desensitization and a direct HLAi

transplant. Data from NHSBT suggests that if a patient has been unsuccessful in obtaining a

match in the UKLDKSS within 4 runs, then success is extremely unlikely (NHSBT data). Our

11

data support this, and indicate that the UKLDKSS, has a limited efficacy for sensitised

patients to achieve a compatible transplant, in keeping with NHSBT data, which suggests

that highly sensitised patients are over represented in the UKLDKSS pool, but under

represented in the patients matched and transplanted through the scheme. Clearly our

study period began at the outset of the UKLDKSS when initial numbers of patients included

in each run was low, and the impact is likely to improve with time. Nevertheless, our data

imply that waiting for a compatible organ might not be in the best interests of all patients; a

prospective study of this group of patients is clearly needed to answer the question of

whether the paired scheme helps in obtaining a compatible transplant.

An important limitation of this and other cohort studies is the possibility of bias, both in

methodology and selection. Given the relatively small survival differences between the

‘Dialysis only’ and ‘Dialysis or transplant’ analysis and the stability of estimates across the

sensitivity analyses, it appears that the results were robust to the post-matching imbalance

in paired scheme status. Even if the matched controls were identical in both their observed

and unobserved characteristics to the HLAi treatment group, these patients may be

different from highly sensitised patients not undergoing treatment. In order to explore the

significance of this bias, information would need to be available on whether or not a wait-

listed patient had a living donor, whether incompatible or not, and the date that the living

donor was deemed suitable for transplantation by the transplanting unit. Such a study

would require prospective observations since this information is not currently part of the

NHSBT database.

Death is a relatively crude, but hard end point, which is commonly used as a

transplantation outcome. For a patient weighing up the risks and benefits of

transplantation, the likelihood of survival and quality of life on or off dialysis, are probably

the most important factors, rather than graft survival. We know that in general, quality of

life improves after transplantation(23), but this topic is currently under prospective

multicentre investigation in the UK(24), and there are good reasons to think that quality of

life measures may be different in highly sensitised patients, in whom such a study has not

been performed.

12

In contrast to our analysis, a recent US multicenter study by Orandi et al suggested a

significant survival benefit for HLAi transplantation compared to remaining on the waiting

list and an even greater benefit compared to remaining on dialysis (14, 17). The

characteristics of our HLAi treatment group appear very similar to the equivalent group in

the US study in terms of age, sex, blood group, number of previous transplants, and

duration of renal replacement. Importantly, the latter was 7·9 years in our cohort and 7·3

in the US cohort. However, a methodological difference is that Orandi et al. constructed a

separate ‘Dialysis only’ matched cohort selecting from the subset of patients who never

received a transplant. We would argue that this approach is likely to have overstated the

benefit of HLAi compared to staying on dialysis because the survival time is not only

dependent on transplant status but also affects the likelihood of receiving a transplant in

the first place as a result of time spent on the waiting list. In other words, a reverse

causality exists between transplant status and survival time. Thus, even if receiving a

transplant did not increase survival, we would expect the ‘Dialysis only’ cohort, as selected

in the aforementioned way, to have inferior survival rates, because, by definition, it

excludes individuals who did not survive long enough on the waiting list to receive a

transplant. In statistical terms, this may be considered to be a variant of immortal time bias

(25, 26). In our analysis, we selected a single matched cohort disregarding subsequent

transplant status. For the comparison of HLAi transplantation versus remaining on dialysis,

we then censored survival of the matched controls at the day of transplant. We believe that

this approach provides a better assessment of survival differences.

Beyond this methodological consideration, we do not believe that the findings by Orandi et

al. can be extrapolated outwith the USA. In fact, the results may be more a reflection of the

quality of dialysis care in the USA than of a distinct advantage of HLAi as a transplant

modality (15). The reason for this difference is not easily explained, but as Foley et al refer

to, they are certainly multifactorial and complex – involving the differences beyond the

technical feats of dialysis provision, and pertaining to the differences in holistic

management of the dialysis patient afforded within different health systems(16).

To this end, our study provides a more circumspect view of the benefit of undertaking HLA-

incompatible transplantation. This transplant modality is not to be undertaken lightly,

since, as we show, there is a higher risk of graft loss, compared to compatible

13

transplantation undertaken in similar patients (Figure 3). Additionally, our data indicate

that, for patients who have not been registered in the paired scheme, at the time of

considering an HLAi transplant, the chance of a compatible living donor transplant from the

paired scheme are best within the 1st year of registration in the UKLDKSS (Appendix Figure

A9). Otherwise, the overall rate of compatible transplantation, whether cDD or cLD,

remains constant over time (Figure 2).

Sensitised patients comprise a significant proportion of the waiting list, and attempts to

improve the chances of deceased donor organ allocation are important steps in achieving

equity of access(27). For some highly sensitised patients, the finding demonstrated by

these data that they are likely to wait for 4 years on dialysis before half of the cohort

receive a compatible transplant may be sufficiently unacceptable to make them willing to

take the risk of an HLAi, while for others this may not be the case. As clinicians, our task is

to inform that choice and further prospective work to understand patient motivations and

concerns, and quality of life issues in this difficult-to-transplant population is needed.

In summary, this is the first European national study to examine the question of survival

after HLAi transplantation, and specifically address the issue of whether highly

immunologically sensitised patients are best served by accepting a living donor HLAi after

desensitization or waiting for a compatible alternative. For patients who opt to wait, the

most likely outcome is to remain untransplanted for at least 4 years. For those who do

choose to go ahead with desensitization and HLAi transplant, their survival is comparable

to those who wait, but there is no benefit.

Acknowledgements:

The authors would like to acknowledge the support of NHSBT, as well as the work of all UK

Transplant units contributing to this database.

The research was funded/supported by the National Institute for Health Research (NIHR)

Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and

King's College London. The views expressed are those of the author(s) and not necessarily

those of the NHS, the NIHR or the Department of Health.

Additional thanks to Jean Kwun for critical manuscript review.

14

Research in context

Evidence before this study

We searched PubMed and Medline, links from published papers and authors’ personal

libraries for studies of the effect of HLAi kidney transplantation on patient survival. The

terms searched for in PubMed were: ‘kidney transplantation AND HLA-incompatible

transplantation AND survival’, ‘kidney transplantation AND positive cross match AND

survival’. Of the 105 studies cited, publications relating to single cases or centres, as well as

combining ABO-incompatible outcomes were excluded. One study was found.

Added value of this study

This study is the first European study to provide robust evidence for survival outcomes for

sensitised patients awaiting a transplant.

Implications of all the available evidence

HLA-incompatible kidney transplantation in the UK confers no greater risk to patient

survival than awaiting a compatible living or deceased donor alternative, but does not

confer a survival benefit either. For sensitised patients with an incompatible (i.e.

crossmatch positive) living donor, it represents the most guaranteed route to

transplantation. While clinicians have focussed on graft and patient survival as measures of

success in transplantation, more study of patient quality of life measures related to dialysis

or transplantation are needed to evaluate the risk-benefit of HLA-incompatible

transplantation in highly sensitised patients who are otherwise likely to remain

untransplanted.

15

Tables

Table 1. Demographics of ‘HLAi’ treatment group compared to matched controls –

matching criteria (Base case analysis)

Characteristic ‘HLAi’n = 213

Matched Controlsn = 852

Difference in means (Ratio of variances)

Age (years)(mean ± SD)

44 (±11) 46 (±12) -1·7 (1)

cRF (%)

median (25th – 75th

percentile)

0 – 20%, as % of group21 – 50%, as % of group 51 – 80%, as % of group80 – 100%, as % of group

96 (79 – 99)

8·94·713·173·2

91 (71 – 97)

8·76·714·370·3

3·4 (1)

0·2-2-1·22·9

Duration of ESRD (years)median (25th – 75th percentile)

7·9 (1·3 – 15·9) 8 (0·9 -15·3) 0 (1)

No of prev tx (% of patients)0123

46·93911·72·3

48·437·912·11 6

-1·51·1-0·40·7

Female (% of patients) 65·7 65·6 0·1

Blood Group(% of patients)

OA

ABB

46·933·315·54·2

47·833·515·53·3

-0·9-0·200·9

Diabetes as primary cause of ESRD (% of patients)

0·5 0·5 0

Length of timeregistered in pairedscheme

0 (not registered)0 – 12 months

>12 months

69·513·616·9

81·38·99·7

-11·84·77·2

16

Table 2. Adjusted absolute and differences in restricted mean patient survival of HLAi compared to matched cohort ‘Listed only’ and ‘Listed or transplant’ in months

Scenario (nHLAi/nmatches ¿ Years

HLAi Listed or transplant

Listed only HLAis relative to ‘Listed or transplant’

HLAis relative to ‘Listed only’

Mean (SE)

Mean(SE)

Mean (SE) Mean (SE)

95%CI Mean(SE)

95%CI

Base

case

ana

lysis

(2

13/8

52)

3 34·4(0·4)

34·7(0·2)

34·5(0·2)

0 2(0 5)

-0·8 to1·2

0(0·5)

-0·9 to0·9

5 56·7(0·8)

56·8(0·4)

56 2(0 5)

0 1(0 8)

-1·5 to1·8

-0·5(0·9)

-2·3 to1·3

7 78·3(1·3)

78 3(0·7)

76·9(1)

-0·1(1·9)

-3·8 to3 5

-1 5(1 9)

-5·3 to2 3

10 to

1 m

atch

ing

(213

/213

0)

3 34·2(0·5)

34(0·2)

33·9(0·2)

-0·2(0·4)

-1 to0·6

-0 3(0 5)

-1 4 to0 7

5 56·1(0·9)

55·3(0 3)

54·6(0 4)

-0·9(1·1)

-3·1 to1·3

-1·4(1)

-3·4 to0·6

7 77·7(1 4)

75·7(0 6)

74·3(0·7)

-2(1·9)

-5·7 to1·7

-3(1·7)

-6·4 to0·3

Coar

sed

exac

t mat

chin

g (1

43/4

718)

3 34 8(0 4)

34·7(0 3)

34·6(0·3)

-0·1(0·5)

-1·1 to0·9

-0·2(0·5)

-1·1 to0·7

5 57(0·9)

56·9(0·6)

56·5(0·7)

-0·1(1·4)

-2·8 to2 6

-0 5(1 1)

-2·6 to1·6

7 78·6(1 5)

78·5(1)

77·6(1·3)

-0·1(2·4)

-4·8 to4·7

-0·9(2·4)

-5·6 to3·8

>85%

cRF

scor

e on

ly

(152

/608

)

3 33·9(0·6)

34·2(0·3)

34(0 3)

0·2(0·7)

-0 7 to1 7

0(0·7)

-1·3 to1·4

5 55·9(1·1)

55·8(0 6)

55 2(0 8)

-0·2(1·6)

-3·2 to2·9

-0·7(1·4)

-3·5 to2

7 77·8(1·8)

76·8(1·1)

75·7(1·4)

-1(2·2)

-5·2 to3·3

-2·1(2)

-6 to1·8

17

References

1. Pruthi R, Hilton R, Pankhurst L, Mamode N, Hudson A, Roderick P, et al. UK Renal Registry 16th annual report: chapter 4 demography of patients waitlisted for renal transplantation in the UK: national and centre-specific analyses. Nephron Clinical practice. 2013;125(1-4):81-98.2. Patel R, Terasaki PI. Significance of the Positive Crossmatch Test in Kidney Transplantation. N Engl J Med. 1969;280(14):735-9.3. Johnson RJ, Allen JE, Fuggle SV, Bradley JA, Rudge C, Kidney Advisory Group UKTN. Early experience of paired living kidney donation in the United kingdom. Transplantation. 2008;86(12):1672-7.4. Sharif A, Kraus ES, Zachary AA, Lonze BE, Nazarian SM, Segev DL, et al. Histologic phenotype on 1-year posttransplantation biopsy and allograft survival in HLA-incompatible kidney transplants. Transplantation. 2014;97(5):541-7.5. Bentall A, Cornell LD, Gloor JM, Park WD, Gandhi MJ, Winters JL, et al. Five-year outcomes in living donor kidney transplants with a positive crossmatch. Am J Transplant. 2013;13(1):76-85.6. Iyer HS, Jackson AM, Zachary AA, Montgomery RA. Transplanting the highly sensitised patient: trials and tribulations. Curr Opin Nephrol Hypertens. 2013;22(6):681-8.7. Warren DS, Montgomery RA. Incompatible kidney transplantation: lessons from a decade of desensitization and paired kidney exchange. Immunol Res. 2010;47(1-3):257-64.8. Sharif A, Zachary AA, Hiller J, Segev D, Alachkar N, Kraus ES, et al. Rescue kidney paired donation as emergency salvage for failed desensitization. Transplantation. 2012;93(7):e27-9.9. Montgomery RA, Lonze BE, Jackson AM. Using donor exchange paradigms with desensitization to enhance transplant rates among highly sensitised patients. Curr Opin Organ Transplant. 2011;16(4):439-43.10. Susal C, Morath C. Current approaches to the management of highly sensitised kidney transplant patients. Tissue Antigens. 2011;77(3):177-86.11. Jackson AM, Leffell MS, Montgomery RA, Zachary AA. A GPS for finding the route to transplantation for the sensitised patient. Curr Opin Organ Transplant. 2012;17(4):433-9.12. Orandi BJ, Garonzik-Wang JM, Massie AB, Zachary AA, Montgomery JR, Van Arendonk KJ, et al. Quantifying the risk of incompatible kidney transplantation: a multicenter study. Am J Transplant. 2014;14(7):1573-80.13. Vo AA, Petrozzino J, Yeung K, Sinha A, Kahwaji J, Peng A, et al. Efficacy, outcomes, and cost-effectiveness of desensitization using IVIG and rituximab. Transplantation. 2013;95(6):852-8.14. Orandi BJ, Luo X, Massie AB, Garonzik-Wang JM, Lonze BE, Ahmed R, et al. Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors. N Engl J Med. 2016;374(10):940-50.15. Goodkin DA, Mapes DL, Held PJ. The Dialysis Outcomes and Practice Patterns Study (DOPPS): How Can We Improve the Care of Hemodialysis Patients? Semin Dial. 2001;14(3):157-9.16. Foley RN, Hakim RM. Why is the mortality of dialysis patients in the United States much higher than the rest of the world? J Am Soc Nephrol. 2009;20(7):1432-5.17. Montgomery RA, Lonze BE, King KE, Kraus ES, Kucirka LM, Locke JE, et al. Desensitization in HLA-Incompatible Kidney Recipients and Survival. N Engl J Med. 2011;365(4):318-26.18. Rosenbaum PR. Risk-Set Matching. Design of Observational Studies. New York, NY: Springer New York; 2010. p. 223-35.19. Ho DE, Imai K, King G, Stuart EA. Matching as Nonparametric Preprocessing for Reducing Model Dependence in Parametric Causal Inference. Political Analysis. 2007;15(3):199-236.20. Royston P, Parmar MK. Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome. BMC medical research methodology. 2013;13:152.21. Hinchliffe SR, Lambert PC. Extending the flexible parametric survival model for competing risks. Stata J. 2012;12:674-87.22. Stuart EA, and Donald B. Rubin. . Best practices in quasi-experimental designs. In: Osborne JW, editor. Best Practices in Quantitative Methods2008. p. 155-76.23. von der Lippe N, Waldum B, Brekke FB, Amro AA, Reisaeter AV, Os I. From dialysis to transplantation: a 5-year longitudinal study on self-reported quality of life. BMC nephrology. 2014;15:191.

18

24. Oniscu GC, Ravanan R, Wu D, Gibbons A, Li B, Tomson C, et al. Access to Transplantation and Transplant Outcome Measures (ATTOM): study protocol of a UK wide, in-depth, prospective cohort analysis. BMJ open. 2016;6(2):e010377.25. Lévesque LE, Hanley JA, Kezouh A, Suissa S. Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes2010 2010-03-12 12:16:39.26. Kim SJ. Immortal Time Bias in Cohort Studies of Kidney Transplant Recipients. Am J Transplant. 2010;10(1):190-.27. Nguyen HD, Wong G, Howard K, Claas FH, Craig JC, Fidler S, et al. Modeling the benefits and costs of integrating an acceptable HLA mismatch allocation model for highly sensitised patients. Transplantation. 2014;97(7):769-74.

19

Appendix Methods & TablesMatching methods involve an implicit trade off between bias and variance and no

approach can be proven to be ‘optimal’ in any specific sample. In our base case analysis

we used mahalanobis distance (MD) matching with a target matching ratio 4 to 1 (1).

Firstly, we simultaneously calculated the MD of the HLAIs with respect to the potential

matches within their respective risk-matching sets. Secondly, we determined the pairing

of treated and matched controls that minimized the total sum of mahalanobis distance

and matched each control to at most one treated unit (2). If there were multiple matches

with the same MD as the largest MD among those selected, we included all of these

observations using sampling weights in the analysis to still obtain the same sum of

sample weights for each HLAi. As an alternative to our base case analysis, we matched

each HLAi recipient with ten rather than four controls using the same MD matching

approach thus effectively relaxing our matching criteria (Table 2). In addition, rather

than matching based on estimated statistical distance between observations we

matched on criteria defined by us using Coarsened Exact Matching (CEM) with a variable

matching ratio (3). In this sensitivity analysis, we effectively matched on stricter criteria

than in the base case analysis but only on a subset of the HLAi cohort (approximately

2/3 of the HLAi sample) for whom such closer matches were available. More specifically,

we divided non-binary matching variables into groups. For age these were 18-29, 30-39,

40-49, 50-59, 60-69 and 70-85 years, for duration of ESRD 0-5, 6-11, 12-23, 24-47, 48-

71 and 72+ months, for duration of listing on paired scheme, 0, 0-12, 12+ months and

for the cRF score 0, 1-59, 60-84, 85- 94 and 95-100. In addition, we matched on whether

patients had a previous transplant, whether diabetes was the primary cause of ESRD,

and matches we required to have the same gender, the same blood type (0, A or other)

in this sensitivity analysis. Subject to at least one match remaining for each HLAi, any

control that was matched to multiple treated patients was assigned to the one with the

lowest MD. Again, we used sampling weights to reweigh the sample depending on the

number of matches per HLAi recipient (Table 3)

26

Appendix Table 1. Mean differences of subgroup analysis of patients with a cRF of >85%





43 (±11) 45 (±11) -2·2 (0·9)

cRF (%)


percentile)

0 – 20%, as % of group21 – 50%, as % of group51 – 80%, as % of group80 – 100%, as % of group

98 (95 – 100)

000100

97 (94 – 99)

000100

0·9 (0·9)

0000


11·1 (3·1 -18·1) 10·9 (3·8 -18·5) -0·2 (0·9)


34·246·715·83·3

3643·318·12·6

-1·8 3·4-2·3 0·7

Female (% of patients) 62·5 60·4 2·1


OA

ABB

48·732·913·84·6

46·934·014·14·9

1·8-1·1-0·3-0·3


0·7 0·7 0



>12 months

62·515·821·7

84·07·48·6

-21·5 8·4 13·1

27

Appendix Table 2: Mean differences of matching run using 10 to 1 matches to index cases





44 ± 11 48 ± 12 -3·1 (1·)

cRF

median (25th – 75th percentile)


96 (79 - 99)

8·94·713·173·2

87 (57 -96)

9·710·916·662·8

7·9 (0 9)

-0·8-6·2-3·510·4


7·9 (1·3 – 15·9) 7 (0·8 – 14·9) 0·3 (1)


46·939·011·72·3

51·335·911·31·5

-4·43·10·40·8

Female (% of patients) 65·7 64·7 1


OA

ABB

46·933·315·54·2

45·834·615·73·9

1·1-1·3-0·2 0·3


0·5 0·5 0



>12 months

69·513·616·9

88·27·24·6

-18·76·412·3

28

Appendix Table 3: Mean differences using Coarsened Exact Matching (CEM) methods





46 (± 12) 46 (± 12) -0 7 (1)

cRF


percentile)


92 (60 – 99)

12·67·017 562 9

91 (61 – 98)

15·36·714·963·1

1·6 (0·9)

-2·7 0·3 2·6-0·2


0·4 (0·1 – 1·2) 0·4 (0 – 1·2) 0 (0·9)


54·530·811·92·8

54 53013·42

0 0·8-1·5 0·8

Female (% of patients) 67·8 67·8 0


OA

ABB

46·936·412·64·2

46·935·912·64·7

00·50-0·5


0 0 0



>12 months

89·55·64·9

89·55·64·9

000

29

References

1. Kantor D. MAHAPICK: Stata module to select matching observations based on a Mahalanobis distance measure. Statistical Software Components2012/11/15/.2. Hansen BB, Fredrickson, M., Fredrickson, M.M.M., Rcpp, L. and Rcpp, I. Package ‘optmatch’. 2016.3. Blackwell M IS, King G, Porro G. Cem: Coarsened exact matching in stata. Stata J 2009;9:524–46. Epub 524.

30

Figure A1. Quantile-quantile plot for calculated reaction frequency (cRF) between HLAi cohort and identified matches (N.B.: for clarity, observation have been randomly perturbed by a small amount)

2040

6080

Age

in y

ears

(HLA

is)

20 40 60 80Age in years (Matched controls)

Figure A2. Quantile-quantile plot showing difference in age between the HLAi cohort and identified matches (N.B.: for clarity, observations have been randomly perturbed by a small amount)

020

4060

8010

0C

RF

scor

e (H

LAis

)

0 20 40 60 80 100CRF score (Matched controls)

31

45.7 1.3

1.8 28.8 0.1 2.7

0.1 15.4

0.2 3.4 0.6

O

A

B

AB

Blo

od g

roup

(HLA

Is)

O A B ABBlood group (Matched controls)

Figure A3. Difference in blood group between HLAi cohort and identified matches

33.3 0.9

1.1 64.7

Female

Male

Gen

der (

HLA

is)

Male FemaleGender (Matched controls)

Figure A4. Difference in gender between HLAi cohort and identified matches

32

44.2 2.6 0.1

4.0 33.8 1.1 0.1

0.1 1.5 10.1

0.8 1.53

2

1

0

Num

ber o

f pre

viou

s tra

nspl

ants

(HLA

is)

0 1 2 3Number of previous treatments (Matched controls)

Figure A5. Difference in number of previous transplants between HLAi and identified matches

010

2030

40D

urat

ion

of E

SR

D in

yea

rs (H

LAis

)

0 10 20 30 40Duration of ESRD in years (Matched controls)

Figure A6. Quantile-quantile plot for time on dialysis between HLAi cohort and identified matches (N.B.: for clarity, observations have been randomly perturbed by a small amount)

33

99.5

0.51

0

Dia

bete

s re

cord

ed a

s pr

imar

yca

use

of E

SR

D (H

LAis

)

0 1Diabetes recorded as primary

cause of ESRD (Matched controls)

Figure A7. Difference in diabetes as primary cause of ESRD between HLAi and identified matches

69.5

4.7 8.9

7.2 9.7

0

0-12

13+Tim

e re

gist

ered

in p

aire

d sc

hem

e in

mon

ths

(HLA

is)

0 0-12 13+Time registered in paired scheme in months (Matched controls)

Figure A8. Differences in time registered in paired scheme between HLAis and matched controls

34

020406080

100

% o

f mat

ched

con

trols

0 12 24 36 48 60 72 84 96Months

Registered <12 monthson the date of matching

020406080

100

% o

f mat

ched

con

trols

0 12 24 36 48 60 72 84 96Months

Registered >12 monthson the date of matching

020406080

100

% o

f mat

ched

con

trols

0 12 24 36 48 60 72 84 96Months

Not registered in the pairedscheme on the date of matching

Transplanted with an LD compatibleTransplanted with a DD compatible

Figure A9. Figure 2. Matched cohort: expected transplant status of matched controls during the study period, with 95% confidence bands. A. transplant status for patients registered in the paired scheme (’UKLDKSS) for less than 1 year on the date of matching. B. transplant status for patients registered for over 1 year in the UKLDKSS for over 1 year on the date of matching in the study. C.

BA

C

35

transplant status for patients not registered in the paired scheme on the date of matching

0

20

40

60

80

100

Pat

ient

sur

viva

l (%

)

2130 1243 755 436 245 141 74 33 0Dialysis only2130 1631 1234 921 674 483 299 155 0Dialysis or transplant213 202 178 147 115 88 48 19 0HLAi transplant

Number at risk

0 12 24 36 48 60 72 84 96Months

HLAi transplant Dialysis or transplantDialysis only

Figure A10. Kaplan-Meyer survival curve comparing HLAi against a matched cohort using 10 to 1 mahalanobis distance matching

0

20

40

60

80

100

Pat

ient

sur

viva

l (%

)

4718 3262 2173 1442 866 527 283 129 0Dialysis only4718 4002 3225 2488 1893 1363 876 414 0Dialysis or transplant143 138 127 103 83 64 38 14 0HLAi transplant

Number at risk

0 12 24 36 48 60 72 84 96Months

HLAi transplant Dialysis or transplantDialysis only

Figure A11. Kaplan-Meyer survival curve comparing HLAi against a matched cohort using coarse exact matching

36

0

20

40

60

80

100

Gra

ft su

rviv

al (%

)

125 86 55 39 27 14DD compatible47 30 19 14 11 6LD compatible151 123 108 87 64 45HLAi transplant

Number at risk

0 12 24 36 48 60Months after transplant

HLAi transplant LD compatibleDD compatible

Figure A12. Comparison of death-censored graft survival in HLAi against a matched cohort of patients receiving a compatible kidney transplant from either a living (cLD) or deceased donor (cDD), subgroup analysis of patients with a cRF of >85%

37

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