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Challenging frontiers in renal transplantation

Peters-Sengers, H.

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Citation for published version (APA):Peters-Sengers, H. (2018). Challenging frontiers in renal transplantation.

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DCD donor hemodynamics

81

CHAPTER 5 CHAPTER 5 CHAPTER 5 CHAPTER 5

DCD DONOR HEMODYNAMICS AS PREDICTOR OF OUTCOME

AFTER KIDNEY TRANSPLANTATION

AuthorsAuthorsAuthorsAuthors

H. Peters-Sengers

J.H.E. Houtzager

M.B.A. Heemskerk

M.M. Idu

R.C. Minnee

R.W. Klaasen

S.E. Joor

J.A.M. Hagenaars

P.M. Rebers

J.J. Homan van der Heide

J.I. Roodnat

F.J. Bemelman

American Journal of Transplantation. 2018 American Journal of Transplantation. 2018 American Journal of Transplantation. 2018 American Journal of Transplantation. 2018 epub ahead of printepub ahead of printepub ahead of printepub ahead of print

Chapter 5

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ABSTRACTABSTRACTABSTRACTABSTRACT

Insufficient hemodynamics during agonal phase—i.e. the period between withdrawal of life-

sustaining treatment and circulatory arrest—in Maastricht category III circulatory-death donors

(DCD) potentially exacerbate ischemia/reperfusion injury. We included 409 Dutch adult

recipients of DCD donor kidneys transplanted between 2006 and 2014. Peripheral oxygen

saturation (SpO2–with pulse oximetry at the fingertip) and systolic blood pressure (SBP–with

arterial catheter) were measured during agonal phase, and were dichotomized into minutes of

SpO2>60% or SpO2<60%, and minutes of SBP>80 mmHg or SBP<80 mmHg. Outcome

measures were primary non-function (PNF), delayed graft function (DGF), and 3-year graft

survival. Primary non-function (PNF) rate was 6.6%, delayed graft function (DGF) rate was 67%,

and graft survival at 3 years was 76%. Longer periods of agonal phase (median 16 min (IQR 11-

23)) contributed significantly to an increased risk of DGF (p=.012), but not to PNF (P=.071) and

graft failure (p=.528). Multiple logistic regression analysis showed that an increase from 7 to 20

minutes in period of SBP<80mmHg was associated with 2.19 times the odds (95%CI 1.08-4.46,

p=0.030) for DGF. In conclusion, duration of agonal phase is associated with early transplant

outcome. SBP<80mmHg during agonal phase shows a better discrimination for transplant

outcome than SpO2<60% does.


83

INTRODUCTIONINTRODUCTIONINTRODUCTIONINTRODUCTION

Renal transplantation of deceased donor kidneys is the preferred type of renal replacement

therapy with respect to patient outcome as compared to long-term dialysis.1 Although the

number of actively listed patients on the renal transplant waiting list is declining in the

Netherlands, the median waiting time for a kidney from a deceased donor is still more than two

and a half years and roughly 10% of patients die on the waiting list.2

In the last 5 years, donation after brain-death (DBD) kidneys and donations after

circulatory-death (DCD) kidneys contribute an equal share in the number of deceased donor

kidneys. DCD donors (Maastricht category III)3 are patients in intensive care units in which

circulatory arrest is awaited after withdrawal from life-sustaining treatment. As opposed to

DBD, the DCD procedure is accompanied with warm ischemia time preceding circulatory

arrest, which may result in a higher incidence of primary non-function (PNF) and delayed graft

function (DGF). There is limited evidence that the hemodynamics during the agonal phase—i.e.

the period between withdrawal of life-sustaining treatment and circulatory arrest—potentially

exacerbate ischemia/reperfusion injury of the DCD kidney. If agonal phase parameters cause

extra ischemic insult, these may be useful to predict recipient transplant outcome.

To minimize the potential impact of duration of agonal phase, our nationwide protocol

from the Dutch Transplant Foundation recommends a cut-off of 2 hours.4 However, consensus

in US was set to 1 hour, and in UK the duration of agonal phase may be up to 5 hours (3 hours

before systolic BP <50mmHg, and 2 hours after systolic BP <50mmHg). In the UK, Reid et al.

studied 117 DCD donors using a cut-off for the agonal phase of 4 hours, and found no

association between duration of agonal phase and transplant outcome.5 It was Ho et al. who

argued that agonal phase characteristics, including duration and severity of hemodynamic

instability or hypoxia may be better predictors of graft function than just the agonal phase

period.6 In another comprehensive study from the US, Allen et al. analyzed different

hemodynamic measures to capture warm ischemic injury from extubation until cross-clamp of

the aorta.7 Surprisingly, they did not find an association between SBP <50mmHg in minutes

during agonal phase and outcome of DGF or graft failure. But as the authors stated, this was

partly due to the nonlinear trajectory of SBP which underestimated the effect on DGF. Once

solved by estimating Area Under the Curve (AUC) of SBP, it was found to be a significant

predictor of DGF. This increased risk was not found for graft failure, implying that agonal phase

characteristics have an immediate effect on the graft, but not on longer-term survival.7 The

duration of agonal phase and hemodynamic measures have not been evaluated in a program

including elderly (≥65 y) DCD kidneys.

In this retrospective cohort study, we sought to address two research questions: 1) How

is duration of agonal phase period associated with transplant outcome? 2) Can measures of

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systolic blood pressure and peripheral oxygenation during agonal phase predict transplant

outcome?

METHODSMETHODSMETHODSMETHODS

Study PopulationStudy PopulationStudy PopulationStudy Population

Data were retrieved from Erasmus Medical Center and Academic Medical Center (AMC), two

Dutch transplant centers that are tertiary referral hospitals in Rotterdam and Amsterdam,

respectively. We included all adult (≥18) recipients (n = 409) of a renal allograft from a DCD

Maastricht category III donor procured between January 1, 2006, and January 1, 2014. Patients

were followed till May 1, 2015, or at the last known serum creatinine measurement.

MeasuresMeasuresMeasuresMeasures

We evaluated several endpoints after transplantation: primary non-function (PNF) (graft never

functioned, recipient lived for at least 10 days after transplantation), delayed graft function

(DGF; need for dialysis within 7 days after transplantation), death-censored graft survival at 3

years, and a composite endpoint for graft failure at 3 years including graft loss, patient death as

well as an estimated transplant glomerular filtration rate (eGFR) below 15 without further

improvement over time (whichever came first).

The following donor–related characteristics were included: age, sex, smoking status

(yes/no), length, weight, use of inotropics prior to donation (yes/no), last measured serum

creatinine, cause of death (trauma capitis; cardiovascular accident; anoxia; brain tumor; trauma

other; other).

Recipient characteristics were: age, dialysis vintage (in days), and primary renal disease

(polycystic kidney disease; glomerulonephritis; renal vascular disease; diabetes; chronic renal

failure (etiology unknown); pyelonephritis; other). Initial immunosuppressive therapy consisted

of induction therapy with basiliximab and steroids combined with mycophenolate mofetil and a

calcineurin inhibitor, mostly tacrolimus but also cyclosporine. Alternatively, a combination of

steroids, tacrolimus, and sirolimus was used.

Transplant-related variables considered for inclusion were: period of agonal phase,

peripheral oxygen saturation (SpO2, measured with pulse oximetry at the fingertip during

agonal phase), systolic blood pressure (SBP, measured by arterial catheter during agonal phase),

donor warm ischemic time (WIT), cold ischemic time (CIT), anastomosis time, and number of

HLA mismatch levels (no mismatch to up to 6 mismatches). Figure 1 depicts the definitions of

measures for donor WIT. Agonal phase was defined as time from withdrawal of life-sustaining

treatment to circulatory arrest. Parameters during agonal phase were dichotomized into minutes

of SpO2 > 60% or SpO2 < 60%, and minutes of SBP > 80 mmHg or SBP < 80 mmHg. These

limits were predefined by our transplant coordinators and registered as such in the registry.


85

Figure 1Figure 1Figure 1Figure 1. Scheme of the controlled DCD donor kidney retrieval with measures for donor warm ischemic injury succeeded by cold ischemic injury from cold perfusion.

During agonal phase, transplant coordinators continuously monitored SpO2 and SBP, and

registered these with clock times in minutes in the Eurotransplant donor procedure application.

Agonal phase measures were explicitly separated from 1st WIT, the time from circulatory arrest

to cold perfusion within the hospital. CIT was defined as the time from start of cold perfusion to

removal from ice for implantation. Anastomosis time was the time during implantation, from

removal of the organ from ice until reperfusion. HLA mismatches were defined as the number of

mismatches between donor and recipient of HLA-A, HLA-B, and HLA-DR combined.

Donor criteria and proceedings of donation after circulatory death Donor criteria and proceedings of donation after circulatory death Donor criteria and proceedings of donation after circulatory death Donor criteria and proceedings of donation after circulatory death

Age limit for the DCD donor is set to 75 years. Permissible time of agonal phase between switch-

off and circulatory arrest is restricted to 120 minutes. The duration of acceptable 1st WIT (time

from circulatory arrest to start) is 30 minutes, including the obligatory 5-minute no touch period

after circulatory arrest. After the obligatory 5-minute no touch period, the deceased was

immediately transported to the operating room from the ICU, where surgical staff were waiting.

A rapid laparotomy and direct cannulation of the aorta was then performed and organs were

procured afterwards.

Statistical AnalysisStatistical AnalysisStatistical AnalysisStatistical Analysis

We compared the donor and recipient characteristics of transplanted patients across the

categories of duration of agonal phase. We used logistic regression for the short-term transplant

outcomes PNF and DGF. Kaplan-Meier curves were used, right-censored at 3 years, to estimate

cumulative death-censored graft survival. Cumulative incidence competing risk (CICR)

functions were used to calculate unadjusted incidences of 3-year graft survival, and to take into

account the competing events of patient death, graft loss, and eGFR<15 without further

improvement over time.8 Loss to follow-up was handled by censoring at the last known date of

creatinine measurement at the hospital. We searched the literature for known donor and

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recipient risk factors that were associated with transplant outcomes of transplanting kidneys

from donors after circulatory death. In addition, these variables had to be documented by either

transplant coordinators in the two hospitals or electronic patient files or Eurotransplant data.

We used these factors in a prediction model for PNF, DGF, and cause-specific Cox-regression

analysis. To avoid categorization, agonal phase period and agonal phase parameters were

modelled with a 3-knot restricted cubic spline with pre-defined internal knots at the median and

interquartile range (IQR). We used Wald tests to describe the effect of prolonged agonal phase

period and its parameters, and to test for linearity. The presence of significance of interaction

was evaluated, and Wald tests were used to estimate the joint effect of the interactions. Since

duration of SBP<80mmHg and SpO2<60% are highly correlated, we conducted separate models

to avoid multicollinearity.

The rate of missing agonal phase data was below 15.0% (table 1). All missing values

were imputed by using the Multivariate Imputation by Chained Equations (MICE) algorithm

with a predictive mean matching (PMM) modeling type for continuous variables. Each missing

variable in MICE is treated as an outcome, and missing data are predicted from the remaining

variables, including graft failure at 3 years, delayed graft function, and renal function at 1 year.

The PMM method ensures that imputed values are plausible, as this method might be more

appropriate than the regression method if the normality assumption is violated. We created ten

imputed datasets and pooled the regression results to take different imputed values into account.

Continuous variables are presented as median ± interquartile range (IQR). Regression

coefficients with corresponding relative risks are reported as odds ratios (ORs) or hazard ratios

(HRs) with 95% confidence intervals (95%CIs). Significance levels were set at the 5% level.

Analyses were conducted using R (version 3.2.4)9 with the rms package (version 4.5-0), and mice

package for imputation (version 2.3). Figures were plotted using GraphPad Prism (version 7·0).

RESULTSRESULTSRESULTSRESULTS

Baseline characteristicsBaseline characteristicsBaseline characteristicsBaseline characteristics

A total of 409 kidneys from category III DCD donors were transplanted between 2006 and 2014

(see Table 1). Median donor age was 55 years (Inter Quartile Range, IQR, 44 – 61.5). Donors

were predominantly male (62%), and had cerebral vascular accident as main cause of death

(41%). Median Kidney Donor Risk Index (KDRI) was 1.3 (IQR 1.0 – 1.6) of which 7.2% had

KDRI >2. None of the donors were HCV positive. Kidneys from 3 donors were transplanted en-

bloc (0.7%), counting as a single transplantation, and no double kidney transplantations were

procured. Median recipient age was 58 (IQR 47 – 65.6), and mostly male (66%). A total of 54

recipients had a previous transplantation (13%). 1st WIT was 16 min at the median, starting from


87

Donor parametersDonor parametersDonor parametersDonor parameters Median(IQR) / N(%)Median(IQR) / N(%)Median(IQR) / N(%)Median(IQR) / N(%) Missing (%)Missing (%)Missing (%)Missing (%)

Age (yr) 55 (44 – 61.5) 0

Sex (male) 252 (61.6%) 0

Serum creatinine (mg/dL) 0.76 (0.58 – 0.93) 0

Hypertension (yes) 95 (24.3%) 18 (4.4%)

Diabetes (yes) 25 (6.2%) 3 (0.7%)

Cause of death 0

- Trauma capitits 63 (15.4%)

- CVA 169 (41.3%)

- Anoxia 106 (25.9%)

- Trauma other 46 (11.2%)

- Tumor (brain) 5 (1.2%)

- Other 20 (4.9%)

Height (cm) 175 (170 – 180) 1 (0.2%)

Weight (kg) 80 (66-86.8) 1 (0.2%)

HCV positivity 0 (0.0%) 0

En-bloc 3 (0.7%) 0

Double 0 (0.0%) 0

Multi-organ-donor (yes)a 238 (58.2%) 0

KDRI 1.3 (1.0 – 1.6) 20 (4.9%)

Transplant and agonal parametersTransplant and agonal parametersTransplant and agonal parametersTransplant and agonal parameters

HLA-A mismatch 7 (1.7%)

0 104 (25.9%)

-1 221 (55.0%)

-2 77 (19.2%)

HLA-B mismatch 7 (1.7%)

0 50 (12.4%)

-1 206 (51.2%)

-2 146 (36.3%)

HLA-DR 7 (1.7%)

0 103 (25.6%)

-1 233 (58.0%)

-2 66 (16.4%)

HLA mismatches 3 (2 – 4) 2 (0.5%)

Table 1.Table 1.Table 1.Table 1. Descriptive statistics of study cohort (n=409 DCD kidney

transplantations)

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circulatory arrest and including the 5 min no-touch period. Median CIT was 16 hours, and 2nd

WIT (anastomosis time) was 30 minutes. Median period of agonal phase was 16 minutes (IQR

11 – 23). The median functional WIT: agonal phase period with systolic blood pressure < 80

mmHg combined with 1st WIT combined, was 25 minutes (IQR 19 – 32).

Duration agonal phase (min) 16 (11 – 23) 23 (5.6%)

Systolic > 80 mmHg (min) 7 (4 – 13) 54 (13.2%)

Saturation > 60% SpO2 (min) 4 (2 – 9) 58 (14.2%)

Systolic < 80 mmHg (min) 7 (4 – 13) 54 (13.2%)

Saturation < 60% SpO2 (min) 10 (6 – 16) 58 (14.2%)

1st WIT (min) 16 (13 – 20) 11 (2.7%)

Cold ischemic time (hrs) 16.0 (12.4 – 19.7) 1 (0.2%)

Anastomosis time (min) 30 (23.8 – 39.3) 7 (1.7%)

Recipient parametersRecipient parametersRecipient parametersRecipient parameters

Age (yr) 58.4 (47 – 65.6) 0

Sex (male) 269 (65.8%) 0

Dialysis vintage (years) 3.6 (2.1 – 4.9) 7 (1.7%)

Previous transplantation 0

- 1st 355 (86.8%)

- 2nd 43 (10.5%)

- More than 2 11 (2.7%)

Cause of renal failure 0

- Polycystic kidney disease 46 (11.2%)

- Glomerulonephritis 64 (15.6%)

- Hypertension 108 (26.4%)

- Diabetes 71 (17.4%)

- Chronic renal failure, etiology unknown 46 (11.2%)

- Membranious nephropathy 5 (1.2%)

- Pyelonephritis 16 (3.9%)

- Other 31 (7.6%)

Follow-up (years) 2.8 (1.0-4.4)

a Donation of lungs, pancreas, or liver were treated as multi-organ-donors.

Table 1.Table 1.Table 1.Table 1. Continued


89

Period of agonal phase and graft failurePeriod of agonal phase and graft failurePeriod of agonal phase and graft failurePeriod of agonal phase and graft failure

At three years after transplantation, patient death as first event was 7.1% (95%CI 4.7-10.1),

whereas 15.6% (95%CI 12.1-12.1) had graft failure leading to dialysis, and 1.2% of patients

(95%CI 0.5-2.7) had an eGFR below 15 ml/min at 3 months without further improvement.

Delayed graft function was prevalent in 255 transplantations (67%), while excluding 27 cases

(6.6%) of primary non-function.

There were 72 cases (15.8%) with agonal phase period exceeding 30 minutes, with only

19 cases (4.9%) exceeding 60 minutes and 8 cases (2.1%) exceeding 90 minutes. If period of

agonal phase was categorized into groups, death-censored graft failure at 3 years revealed no

differences (p=0.206) (see figure 2). This is also depicted in figure 3A: increase in agonal phase

period was not associated with hazard on graft failure censored for death at 3 years (Wald

p=0.670), neither after adjustments (Wald p=0.734). In contrast, increase in period of agonal

phase significantly predicted the odds of having delayed graft function (Wald p<0.001). The

effect remained significant after adjusting for covariates (Wald p=0.016) (see Figure 3B). An

increase from 16.4 minutes to 40 minutes in period of agonal phase was associated with 1.61

times the odds (95%CI 1.12-2.32, p=0.010) for delayed graft function, and with a trend to

significance for primary non-function (OR 1.56 (95%CI 0.99-2.49, p=0.055) (see Figure 3C).

Figure 2.Figure 2.Figure 2.Figure 2. Death-censored graft survival at 3 years with Kaplan Meier indicate no significant differences according to period of agonal phase (Log-rank, p=0.206).

0.0 0.5 1.0 1.5 2.0 2.5 3.0

0.0

0.2

0.4

0.6

0.8

1.0

Time (years)

Death

-censore

d G

raft

Surv

ival

Agonal phase (min)

<10

10-<1515-<20

20-<30

30+

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Figure 3.Figure 3.Figure 3.Figure 3. Flexible associations of agonal phase period in A) 3-year death-censored hazard on graft failure, B) odds of having primary non-function, and C) odds of having delayed graft function. In all 3 models restricted cubic splines were used to plot period of agonal phase with internal knots at 5, 15 , and 40 minutes, and corresponding to a donor age of 55 y, cold ischemic time of 16 hours, 3 HLA mismatch levels, 16 min 1st WIT, 30 min anastomosis time, CVA as donor cause of death, 67 ml/min last measured creatinine of the donor, multi-organ-donor, 3.6 years recipient dialysis vintage, and recipient age of 58 y.


91

SBP during agonal phase and transplant outcomes SBP during agonal phase and transplant outcomes SBP during agonal phase and transplant outcomes SBP during agonal phase and transplant outcomes

During the agonal phase, the initial period of SBP>80 mmHg was longer than the period of

SpO2>60% (7 min vs. 4 min, p<0.001, respectively). Subsequently, the period SBP stayed <80

mmHg was shorter as compared to SpO2<60% (7 min vs. 10 min, p<0.001, respectively). Figure

4 shows the distribution of different trajectories for SBP and SpO2 from switch-off till

circulatory arrest.

Firstly we tested interaction on a multiplicative scale of period SBP>80mmHg and

SBP<80mmHg, which was not significant for PNF and DGF (adjusted interaction OR 1.012,

95%CI 0.925-1.108, p=0.790, and OR 1.043, 95%CI 0.946-1.150, p=0.395, respectively).

Hereafter, models tested the additive effect of longer periods of both SBP>80mmHg and

SBP<80mmH. Longer period of SBP<80mmHg—modelled with a 3-knot restricted cubic

spline—did not contribute significantly to the prediction of PNF (Wald p=.705), depicted in

Figure 5A. Also the preceding period of SBP>80mmHg did not contribute to predict PNF. In

contrast, longer period of SBP<80mmHg was significantly associated with DGF (Wald p=0.042).

An increase from 7 minutes to 20 minutes in period of SBP<80mmHg was associated with 2.19

times the odds (95%CI 1.08-4.46, p=0.030) for delayed graft function. Increasing period of

preceding SBP>80mmHg did not contribute to predict DGF. Independent of both SBP, we

identified donor age per year, and dialysis vintage per year prior to transplantation as significant

contributors to predict DGF (p=0.047, and p<0.001, respectively). Longer period of

SBP<80mmHg was not significantly associated with long term graft survival and death-censored

graft survival (Wald p=0.399, Wald p=0.596, respectively).

Figure 4.Figure 4.Figure 4.Figure 4. Trajectories from switch-off till cardiac arrest in combination of period of oxygen saturation (SpO2) above 60 % and below 60%, and combination of period of systolic blood pressure (SBP) above 80 mmHg and below 80 mmHg. The median cutoffs were <5 min for short and ≥5 min for long period of >60% SpO2, and for SpO2<60% median cut-offs were <10 min for short and ≥10 min for long period. The median cutoffs were <7 min for short and ≥7 min for long period of >80mmHg SBP, and for SBP<80mmHg median cut-offs were <7 min for short and ≥7 min for long period.

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SpO2 during agonal phase and transplant outcomesSpO2 during agonal phase and transplant outcomesSpO2 during agonal phase and transplant outcomesSpO2 during agonal phase and transplant outcomes

Firstly we tested interaction for SpO2>60% and SpO2<60% which was not significant for PNF

and DGF (adjusted interaction OR 1.013, 95%CI 0.982-1.045, p=0.418, and OR 1.006, 95%CI

0.947-1.069, p=0.837, respectively). Hereafter, models tested the additive effect of longer periods

of both SpO2>60% and SpO2<60%. Longer period of SpO2<60%—modelled with a 3-knot

restricted cubic spline—did not contribute significantly to the prediction of PNF (p=.107),

depicted in Figure 5B. Also the preceding period of SpO2>60% did not contribute to predict

PNF. Longer period of SpO2<60% was also not significantly associated with DGF (p=0.382, but

this was the case for increasing period of SpO2>60% (p=0.032). An increase from 5 minutes to

10 minutes in period of SpO2>60% was associated with 1.20 times the odds (95%CI 1.02-1.41,

p=0.029) for delayed graft function. Independent of both SpO2%, we also identified donor age

per year, and dialysis vintage per year prior to transplantation as significant contributors to

predict DGF (p<0.032, p<0.001, respectively). Longer period of SpO2<60% was not significantly

associated with graft survival and death-censored graft survival (Wald p=0.399, Wald p=0.596,

respectively).

Measures for donor warm ischemic injury, donor age, and transplant outcomesMeasures for donor warm ischemic injury, donor age, and transplant outcomesMeasures for donor warm ischemic injury, donor age, and transplant outcomesMeasures for donor warm ischemic injury, donor age, and transplant outcomes

Functional WIT, starting from SBP<80mmHg to cold perfusion, significantly predicted DGF,

while this was not significant if calculated from SpO2<60% to cold perfusion (see Table 2). Also

the total WIT, starting from withdrawal life-sustaining treatment to cold perfusion, significantly

predicted delayed graft function. These measures for WIT were not able to significantly predict

primary non-function, renal function at 3 months, and graft failure at 3 year. Only time from

asystole to cold perfusion predicted significantly primary non-function: an increase from 10

minutes to 20 minutes was associated with 7.69 times the odds (95%CI 1.01-58.72, p=0.048).

With DGF as outcome, we sought to find associations of agonal phase and functional WIT—

starting from SBP<80mmHg to cold perfusion—for different donor ages with interaction

analyses. Higher donor age attenuated the association of agonal phase as well as for functional

WIT (see Table 3). These findings suggest that for DCD donor kidneys of 60 years and older,

duration of agonal phase and functional WIT are relatively less relevant compared to younger

donors with outcome of DGF.


93

Figure 5.Figure 5.Figure 5.Figure 5. Flexible associations of period SBP<80mmHg from switch-off till cardiac arrest and PNF (A) and DGF (C), and associations of period that SpO2<60% with PNF (B) and DGF (D). In all 4 models restricted cubic splines were used to plot period of SBP<80mmHg and SpO2<60% with internal knots at 5, 10, and 15 minutes. All models were adjusted for at the median of SBP>80mmHg (7 min) or SpO2>60% (5 min). Only DGF models were additionally adjusted, corresponding to a donor age of 55 y, cold ischemic time of 16 hours, 3 HLA mismatch levels, 16 min 1st WIT, 30 min anastomosis time, CVA as donor cause of death, 67 ml/min last measured creatinine of the donor, multi-organ-donor, 3.6 years recipient dialysis vintage, and recipient age of 58 y.

A

C

B

D

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Primary non-functionPrimary non-functionPrimary non-functionPrimary non-functionAAAA

Models Median (IQR)Contribution

Wald test χ2d.f. P value

1st WIT, from asystole to cold perfusion 16 (13-20) 10.3 2 0.001*

Functional WIT, from SBP<80mmHg to cold perfusion 25 (19-32) 5.17 2 0.076

Functional WIT, from SpO2<60% to cold perfusion 27 (22-35) 4.83 2 0.09

Total WIT, from withdrawal to cold perfusion 34 (26-43) 4.29 2 0.117

Agonal phase, from withdrawal to circulatory arrest 16 (11-23) 5.16 2 0.076

SBP<80mmHg (min) during agonal phase 7 (4-13) 0.21 2 0.705

SpO2<60% (min) during agonal phase 4 (2-9) 4.53 2 0.107

Delayed graft functionDelayed graft functionDelayed graft functionDelayed graft functionCCCC


Wald test χ2d.f. P value

1st WIT, from asystole to cold perfusion 13 (16-20) 2.49 2 0.289

Functional WIT, from SBP<80mmHg to cold perfusion 24 (19-32) 7.39 2 0.025*


Total WIT, from withdrawal to cold perfusion 33 (25-43) 8.73 2 0.013*

Agonal phase, from withdrawal to circulatory arrestB 16 (11-23) 6.41 2 0.041*

SBP<80mmHg (min) during agonal phaseB 7 (4-13) 6.31 2 0.042*

SpO2<60% (min) during agonal phaseB 4 (2-9) 2.23 2 0.328

eGFR at 3 monthseGFR at 3 monthseGFR at 3 monthseGFR at 3 monthsDDDD


ANOVA (F)d.f. P value





Agonal phase, from withdrawal to circulatory arrestB 16 (11-23) 0.73 2 0.482

SBP<80mmHg (min) during agonal phaseB 7 (4-13) 2.4 2 0.093


Graft failure at 3 yearsGraft failure at 3 yearsGraft failure at 3 yearsGraft failure at 3 yearsEEEE


Wald test χ2 d.f. P value





Agonal phase, from withdrawal to circulatory arrestB 16 (11-23) 0.96 2 0.618

TableTableTableTable 2.2.2.2. Results of Logistic regression analysis of the influence of donor WIT of DCD donor kidney

transplants (N=409) with outcomes


95

Table 2.Table 2.Table 2.Table 2. Continued Graft failure at 3 yearsGraft failure at 3 yearsGraft failure at 3 yearsGraft failure at 3 yearsEEEE


Wald test χ2 d.f. P value

SBP<80mmHg (min) during agonal phaseB 7 (4-13) 2.36 2 0.308


Note. Models are adjusted, corresponding to a donor age of 55 y, cold ischemic time of 16 hours, 3 HLAmismatch

levels, 30 min anastomosis time, CVA as donor cause of death, 67 ml/min last measured creatinine of the donor,

multi-organ-donor, 3.6 years recipient dialysis vintage, and recipient age of 58 y. Restricted cubic splines are used

with 3 defined internal knots at the median and IQR of the predictor variable. D.f. = degrees of freedom. * indicate

p<0.05.

A = Only univariate results are shown due to small sample of 27 cases of PNF

B = Also adjusted for 1

st WIT at 16 min, time from asystole to cold perfusion

C = PNF cases (n=27) are excluded

D = Graft failure cases <3 months (n=35) are excluded. eGFR calculated with MDRD formula.

E= composite endpoint used for graft failure (graft loss, patient death or eGFR<15 without improvement after

transplantation)

Agonal phaseAgonal phaseAgonal phaseAgonal phaseAAAA Agonal phaseAgonal phaseAgonal phaseAgonal phase

AAAA Agonal phaseAgonal phaseAgonal phaseAgonal phaseAAAA

Donor age OR (95%CI) P value OR (95%CI) P value OR (95%CI) P value

30 3.77 (1.14-10.11) 0.008* 8.75 (1.90-40.31) 0.005* 10.07 (1.92-52.83) 0.006*

40 2.47 (1.21-5.01) 0.013* 4.58 (1.53-13.69) 0.006* 5.86 (1.79-19.15) 0.003*

50 1.61 (0.93-2.79) 0.087 2.39 (1.05-5.48) 0.039* 3.41 (1.37-8.48) 0.008*

60 1.06 (0.58-1.93) 0.86 1.25 (0.51-3.05) 0.621 1.98 (0.72-5.48) 0.187

70 0.69 (0.30-1.59) 0.384 0.65 (0.19-2.24) 0.499 1.15 (0.28-4.77) 0.843

Functional WITFunctional WITFunctional WITFunctional WITBBBB Functional WITFunctional WITFunctional WITFunctional WIT

BBBB Functional WITFunctional WITFunctional WITFunctional WITBBBB

25 min vs. 15 min 35 min vs. 15 min 45 min vs. 15 min


30 1.71 (0.64-4.58) 0.282 4.51 (0.90-22.56) 0.067 n.a.

40 1.49 (0.75-2.98) 0.259 3.11 (0.98-9.85) 0.053 n.a.

50 1.30 (0.78-2.17) 0.322 2.15 (0.97-4.74) 0.058 3.97 (0.76-20.8) 0.103

60 1.13 (0.64-1.98) 0.675 1.48 (0.73-2.99) 0.272 2.09 (0.77-5.69) 0.15

70 0.98 (0.44-2.18) 0.962 1.02 (0.39-2.68) 0.963 1.10 (0.32-3.72) 0.881

Note. PNF cases were removed from DGF analyses (27 cases). N.a. = not available due to low sample size in this

group. Models are adjusted, corresponding to a cold ischemic time of 16 hours, 3 HLA mismatch levels, 30 min

anastomosis time, CVA as donor cause of death, 67 ml/min last measured creatinine of the donor, multi-organ-

donor, 3.6 years recipient dialysis vintage, and recipient age of 58 y. Restricted cubic splines are used with 3 defined

internal knots at the median and IQR of the predictor variable. Only Agonal phase models were additionally adjusted

for 1st WIT, time from asystole to cold perfusion. * indicate p<0.05.A = time from withdrawal treatment to circulatory arrest.

B = time from SBP<80mmHg to cold perfusion.

TableTableTableTable 3.3.3.3. Odds for DGF according to different DCD donor age and duration of agonal phase and

functional WIT


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DISCUSSIONDISCUSSIONDISCUSSIONDISCUSSION

The current study contributes to the existing knowledge about the donors’ period of agonal

phase, and measures of warm ischemic injury. In 409 DCD donor kidney transplantations, only

8 cases exceeded 90 minutes of agonal phase which was within the limit of two hours. Longer

periods of agonal phase were associated with a significantly increased risk of delayed graft

function, and tended to an increased risk of primary non-function though this failed

significance. Agonal phase duration was not associated with death-censored graft failure at three

years. We analyzed two frequently used parameters during agonal phase: minutes of SpO2 > 60%

or SpO2 < 60%, and minutes of SBP > 80 mmHg or SBP < 80 mmHg. We found that duration of

SBP<80mmHg was associated with increased risk of delayed graft function. In DCD donor

kidneys of 60 years and older, duration of agonal phase and functional WIT, starting from

SBP<80mmHg to cold perfusion, showed to be less important compared to younger donors with

outcome of DGF. Surprisingly, period of SpO2<60% was not associated with increased risk of

delayed graft function, however, period of SpO2>60% did significantly influence risk of DGF.

Agonal phase parameters as measured in this study were not significantly associated with

primary non-function, renal function at 3 months, and graft failure at 3 years.

Although it has been suggested that recipients of DCD kidneys with DGF experienced a

higher incidence of overall and death-censored graft loss compared with those without DGF10, in

our cohort the patients with DGF and without DGF had equivalent graft survival and long-term

renal function. Neither of the donor hemodynamic measures during agonal phase predicted

primary non-function, renal function at 3 months nor graft failure at 3 years, with exception of

DGF which is in line with few other investigations available to date. Ho and colleagues (2008)

analyzed SBP<70mmHg and SBP<60mmHg during agonal phase in 134 DCD donor kidney

transplants, showing a trend toward predicting DGF.6 Including 409 transplants, we were able to

conform that hypotension during agonal phase increased the risk for DGF. It is likely that the

small number of events of primary non-function prevented us to reach significance. Allen and

colleagues (2015) studied duration as well as the slope and the area under the curve to

characterize warm ischemic injury in 1050 DCD donor kidneys. They found no association of

duration of SBP<50mmHg and SpO2<75% with DGF and graft failure.7 When they took

linearity of the trajectory into account by calculating the AUC of SBP, AUC of only SBP above

the median showed to be independently associated with DGF. We were not able to calculate

AUC of SBP during agonal phase. Instead, to take non-linearity of association into account, we

introduced restricted cubic splines. The advantage of this method is the facilitation to explore

the relationship with outcomes.

It has been suggested that donor WIT may have higher impact on transplant outcome

in older vs. younger DCD donor kidneys recipients.7 In contrast to Allen et al., (2015) and Ho et

al., (2008), our cohort consist of DCD donors with higher age, up to 78 years, with high KDRI


97

and high incidence of DGF (67%) which enabled us to find differences that relate to donor age.6,7

Arguably, the odds for DGF were already increased for DCD donor kidneys aged >60 years,

leading to attenuation of the association of agonal phase, and to some extend also for functional

WIT. An opposite trend was observed for the composite endpoint of graft failure at 3 years;

longer periods of agonal phase (5 min vs. 60 min) with use of kidneys recovered from older

DCD donors showed higher hazard of graft failure compared with younger donors. These results

suggest that donor WIT may affect the transplant outcomes differentially according to DCD

donor age. Other studies have shown that higher donor WIT was associated with graft failure,

but not necessarily specifically for marginal DCD kidneys.11-13

We show that relatively simple measurements of duration of donor WIT did not

predict 3-month renal function and graft failure on the long-term. The interplay of donor (e.g.

warm ischemic injury and inflammatory signaling) and recipient (reperfusion injury and innate

and adaptive immune response) derived factors might be far more complex. Counterintuitively,

SpO2>60% was shown to be associated with increased odds of DGF, and not SpO2<60%. This

suggests that longer period of SpO2>60%, and thus a more gradual decline in peripheral oxygen

saturation has negative impact on the kidney. As we corrected for other donor confounders, this

result is not readily explainable given that there is still circulation in this period.

Counterintuitive associations of duration of SpO2 and SBP with graft failure were previously

described, as was also suggested that WIT based on duration of hemodynamic measures may not

be optimal.7 It has been suggested that brief, reversible episodes of ischemia in one coronary bed

may trigger protective factors preventing the kidney from reperfusion injury.14 These episodes

were not included in times of donor WIT, and times may reflect different underlying

mechanisms.

Blood pressure can be reliably measured by means of an arterial catheter. However,

peripheral oxygen saturation measurement by means of pulse oximetry at the fingertip may

reflect oxygenation if the kidney accurately, since peripheral vasoconstriction is common in

hemodynamically instable patients in agonal phase.15 Moreover pulse oximeters are less accurate

when oxygen saturation is very low (beneath ~80%).16,17

Our findings suggest that DCD donors with an agonal phase period longer than 1 hour

can be accepted for kidney transplantation, which is in line with other studies.5,18,19 Most recently

a US study by Scalea et al. (2017) showed no differences in graft survival at 8 years between DCD

kidneys within different categories of agonal phase periods with an upper limit of 2 hours. In

another US center with more liberal protocol (upper agonal phase limit of 4 hours), Reid et al.

(2011) also did not find graft survival differences between agonal phase duration <1 hour

compared with >1 hour. When speculating, agonal phase may be increased to 3 or 4 hours,

however, it may be questioned whether changing the upper limit to 3 or 4 hours is likely to

increase the number of DCD donors at a satisfying number that outweigh the costs. In 2016 in

the Netherlands, 159 DCD procedures had been started of which 109 DCD donations were

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effectuated. Of the 50 procedures that were not effectuated, 31 DCD donors did not fulfill the

criteria of the 2 hour standby-time. Handling an upper limit of 4 hours, the donor pool could be

extended with only 2 to 3 eligible DCD donors. The duration of agonal phase is hard to predict20,

and can last for more than 72 hours. The costs of increasing the limit are related to the recovery

teams who have to stand-down longer times.18

Our results are limited in using arbitrary thresholds for systolic blood pressure (<80

mmHg) and saturation (SpO2<60%). Other studies suggest to use thresholds for systolic blood

pressure of <50 mmHg or saturation <80%6,7,21, however, to our knowledge this has not been

proven yet22. Also some studies include minutes of SBP below a certain threshold (mostly 50

mmHg) to the 1st WIT, referred to as functional WIT21. This may be attractive for the purpose of

prediction, but may be less feasible to explore associations. Some other limitations should be

considered. Firstly, we were unable to adjust for possible confounders for outcome of primary

non-function. Secondly, it is likely that more selection bias is present for DCD donor kidneys

with longer periods of agonal phase. The present study showed result from the era of static cold

storage (SCS).

We conclude that duration of agonal phase is associated with early, but not with long

term transplant outcome. Low SBP during agonal phase does influence short term transplant

outcome, though low SpO2 measured with pulse oximetry does not. Agonal phase and its

parameters require research attention to expand the DCD donor pool safely.

REFERENCESREFERENCESREFERENCESREFERENCES

1. Snoeijs MG, Schaubel DE, Hene R, et al. Kidneys from Donors after Cardiac Death Provide Survival

Benefit. Journal of the American Society of Nephrology. 2010;21(6):1015-1021.

2. Nederlandse Transplantatie Stichting. Annex of stats and figures 2002 (In Dutch: Cijferbijlage 2002).

2003.

3. Kootstra G, Kievit JK, Heineman E. The non heart-beating donor. British medical bulletin.

1997;53(4):844-853.

4. Nederlandse Transplantatie Stichting. Protocol for deceased organ and tissue donation (In Dutch:

Modelprotocol postmortale orgaan- en weefseldonatie). 2017;Version 9.6.

https://www.transplantatiestichting.nl/sites/default/files/modelprotocol_postmortale_orgaan-

_en_weefseldonatie.pdf.

5. Reid AW, Harper S, Jackson CH, et al. Expansion of the kidney donor pool by using cardiac death

donors with prolonged time to cardiorespiratory arrest. American journal of transplantation.

2011;11(5):995-1005.

6. Ho KJ, Owens CD, Johnson SR, et al. Donor postextubation hypotension and age correlate with

outcome after donation after cardiac death transplantation. Transplantation. 2008;85(11):1588-1594.

7. Allen MB, Billig E, Reese PP, et al. Donor Hemodynamics as a Predictor of Outcomes After Kidney

Transplantation From Donors After Cardiac Death. American journal of transplantation. 2015.

8. Klein JP, Moeschberger MV. Survival Analysis: techniques for Censored and Truncated Data: Statistics

for Biology and Health. 2nd ed. New York: Springer; 2003.

9. R Core Team. R: A Language and Environment for Statistical Computing. 2016.


99

10. Lim WH, McDonald SP, Russ GR, et al. Association between delayed graft function and graft loss in

donation after cardiac death kidney transplants - a paired kidney registry analysis. Transplantation.

2016.

11. Summers DM, Johnson RJ, Hudson A, Collett D, Watson CJ, Bradley JA. Effect of donor age and cold

storage time on outcome in recipients of kidneys donated after circulatory death in the UK: a cohort

study. Lancet. 2013;381(9868):727-734.

12. Gill J, Rose C, Lesage J, Joffres Y, Gill J, O'Connor K. Use and Outcomes of Kidneys from Donation

after Circulatory Death Donors in the United States. Journal of the American Society of Nephrology.

2017.

13. Singh SK, Kim SJ. Does expanded criteria donor status modify the outcomes of kidney transplantation

from donors after cardiac death? American journal of transplantation. 2013;13(2):329-336.

14. Heusch G, Botker HE, Przyklenk K, Redington A, Yellon D. Remote ischemic conditioning. J Am Coll

Cardiol. 2015;65(2):177-195.

15. Schnapp LM, Cohen NH. Pulse oximetry. Uses and abuses. Chest. 1990;98(5):1244-1250.

16. Severinghaus JW, Naifeh KH. Accuracy of response of six pulse oximeters to profound hypoxia.

Anesthesiology. 1987;67(4):551-558.

17. Thrush D, Hodges MR. Accuracy of pulse oximetry during hypoxemia. South Med J. 1994;87(4):518-

521.

18. Scalea JR, Redfield RR, Arpali E, et al. Does DCD Donor Time-to-Death Affect Recipient Outcomes?

Implications of Time-to-Death at a High-Volume Center in the United States. American journal of

transplantation. 2017;17(1):191-200.

19. Sohrabi S, Navarro A, Wilson C, et al. Renal graft function after prolonged agonal time in non-heart-

beating donors. Transplantation proceedings. 2006;38(10):3400-3401.

20. Wind J, Snoeijs MGJ, Brugman CA, et al. Prediction of time of death after withdrawal of life-sustaining

treatment in potential donors after cardiac death. Critical care medicine. 2012;40(3):766-769.

21. Thuong M, Ruiz A, Evrard P, et al. New classification of donation after circulatory death donors

definitions and terminology. Transplant international. 2016;29(7):749-759.

22. Bradley JA, Pettigrew GJ, Watson CJ. Time to death after withdrawal of treatment in donation after

circulatory death (DCD) donors. Current opinion in organ transplantation. 2013;18(2):133-139.

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SUPPLEMENTSSUPPLEMENTSSUPPLEMENTSSUPPLEMENTS

Agonal phaseAgonal phaseAgonal phaseAgonal phaseAAAA Agonal phaseAgonal phaseAgonal phaseAgonal phase

AAAA Agonal phaseAgonal phaseAgonal phaseAgonal phaseAAAA


30 n.a. n.a. n.a.

40 3.44 (0.30-38.80) 0.318 n.a. n.a.

50 2.80 (0.63-12.35) 0.175 3.69 (0.46-29.65) 0.039* 1.17 (0.04-31.78) 0.008*

60 2.27 (0.74-6.95) 0.15 3.64 (0.65-20.52) 0.621 3.36 (0.52-21.56) 0.187

70 1.85 (0.33-10.44) 0.487 3.60 (0.26-50.34) 0.499 n.a. 0.843

Functional WITFunctional WITFunctional WITFunctional WITBBBB Functional WITFunctional WITFunctional WITFunctional WIT

BBBB Functional WITFunctional WITFunctional WITFunctional WITBBBB



30 1.84 (0.07-47.32) 0.712 n.a. n.a.

40 1.94 (0.20-18.70) 0.567 3.03 (0.24-38.41) 0.393 n.a.

50 2.04 (0.46-9.05) 0.348 2.94 (0.54-16.06) 0.212 3.63 (0.64-20.75) 0.147

60 2.15 (0.57-8.15) 0.261 2.86 (0.59-13.97) 0.193 3.08 (0.68-14.01) 0.145

70 2.26 (0.32-15.96) 0.413 2.78 (0.28-28.14) 0.386 2.61 (0.28-24.12) 0.397

N.a. = not available due to low sample size in this group. * indicate p<0.05.


Note. Models are not adjusted for other confounders due to low number of PNF cases.

A = time from withdrawal treatment to circulatory arrest.

B = time from SBP<80mmHg to cold perfusion.

TableTableTableTable S1.S1.S1.S1. Odds of PNF according to different DCD donor age and duration of agonal phase and

functional WIT

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