Living kidney donor evaluation and safety assessment
van Londen, Marco
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Estimated GFR before Living
Kidney Donation and
Post-donation Measured GFR
Marco van Londen1*, MD; Jessica van der Weijden1*, Robert S. Niznik2,
MD; Stephan J.L. Bakker1, MD, PhD; Stefan P. Berger1, MD, PhD; Jan Stephan F.
Sanders1, MD, PhD; Gerjan Navis1, MD, PhD; Andrew D. Rule2, MD, MSc; and
Martin H. de Borst1, MD, PhD
In preparation
1 Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical
Center Groningen and University of Groningen, Groningen, the Netherlands
2 Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN,
Abstract
In living kidney donor screening, precise renal function measurements are vital to minimize donor ESRD risk. Although measured GFR (mGFR) is the gold standard renal function test, it is costly and laborious, and replacement by estimated GFR (eGFR) would be desirable. We therefore tested the capacity of pre-donation eGFR equations to predict post-donation mGFR and calculated eGFR cut-off for donor selection.
In 873 living donors who donated in our center between 1984 and 2017, we prospectively measured pre- and post-donation creatinine-based eGFR (CKD-EPI, Cockcroft-Gault, MDRD), 24 hour urinary creatinine clearance and mGFR (continuous iotholamate). We calculated bias and used linear regression to test the performance of the different eGFR formulas. We also calculated pre-donation eGFR cut-offs for post-donation mGFR with a 95% probability.
Mean donor age was 53±12 years, 48% of donors were male. Pre-donation mGFR was 102±16 mL/min/1.73m2 and short-term post-donation mGFR was 65±11 mL/min/1.73m2.
The pre-donation eGFRCKD-EPI threshold to predict a post-donation mGFR >50 mL/ min/1.73m2 with 95% probability was 94 mL/min/1.73m2, indicating that donors with a
pre-donation eGFRCKD-EPI of minimally 94 mL/min/1.73m2 (33% of donors) do not require mGFR
confirmation to achieve a post-donation single-kidney mGFR above 50 mL/min/1.73m2.
We show that eGFR can be used in a subgroup of donors with a high probability of good post-donation renal function without requiring mGFR measurement. The mGFR remains important in the majority of donors with an eGFR below these cut-offs values.
2
Introduction
Living donor kidney transplantation is the treatment of choice for patients with end-stage renal disease (ESRD)1,2. As a consequence of donor organ shortage, selection criteria for
potential living kidney donors have been liberalized3.
To minimize the life-time post-donation ESRD risk, all living kidney donor candidates undergo a screening procedure prior to donation, which includes an estimation of the glomerular filtration rate (GFR). The method of GFR estimation varies among centers, and may include the creatinine clearance (CrCl), creatinine-based estimated GFR (eGFRcr) using one of the available equations, or a true GFR measurement using exogenous filtration markers to obtain the measured GFR (mGFR). While the mGFR measurement is considered the gold standard, the technique is time-consuming and expensive. The 2017 KDIGO guideline for the evaluation and follow-up of living kidney donors suggests using a creatinine-based eGFR (eGFRcr) formula as initial assessment tool for living kidney donors4. This suggestions
is based on a study comparing eGFRCKD-EPI and mGFR in the CKD-EPI collaboration cohort5.
Although, this study indicated that the eGFRcr can be considered accurate, it also concluded that it is imprecise, particularly in the higher GFR range. This may cause under- and overestimation of GFR in healthy individuals, thereby reducing the utility of eGFRcr for living donor screening. The KDIGO guideline provides a general GFR cut-off, but does not specify if this should be estimated or measured GFR. Despite a useful calculator that can be used to calculate posttest probabilities for eGFRcr6,7, to date clinicians still have to extrapolate
eGFRcr values to individual decisions without clear guidance on if and when a confirmatory test is necessary.
The ultimate goal of GFR measurements in donor screening is to predict renal function for the remaing single kidney after donation. It is unknown whether pre-donation eGFR is also suitable for predicting post-donation donor renal function. We therefore tested the performance of pre-donation eGFR to predict post-donation mGFR. We also investigated which commonly used eGFR estimations best predicts post-donation mGFR and compared the results with the creatinine clearance.
Methods
Study design and population
In this prospective cohort study, we performed mGFR measurements in 873 living kidney donors who donated between 1982 and 2017 in the University Medical Center Groningen,
The Netherlands. The mGFR was measured as the urinary clearance of 125I-iothalamate 4
months before donation and at 7 weeks, 5 years and 10 years after living kidney donation, all as part of the screening program and post-donation evaluation8. The study was approved
by the institutional ethical review board (METc 2014/077). All procedures were conducted in accordance with the declaration of Helsinki and declaration of Istanbul.
As a result of our donor selection criteria all donors were normotensive or had an adequately regulated blood pressure while taking no more than two classes of antihypertensive drugs). Furthermore, individuals with a history of diabetes (or an abnormal glucose tolerance test), kidney disease or cardiovascular events were not allowed to donate. Any other condition that was considered a potential threat to long-term renal or cardiovascular outcome was considered a contra-indication for donation, at the discretion of the nephrologist involved in the selection procedure.
Laboratory measurements
Serum creatinine was measured routinely in our clinical chemistry laboratory by an isotope dilution mass spectrometry (IDMS) traceable enzymatic assay on the Roche Modular (Roche Ltd., Mannheim, Germany) from 1st March 2006 onwards. Before this date, samples were
measured by Jaffé alkaline picrate assay on the Merck Mega Analyzer (Merck, Darmstadt, Germany). Values obtained by the Jaffé method were converted to allow comparison with the Roche method by the formula (YRoche =(XJaffé -8)/1.07). Creatinine clearance was
calculated from the 24-hour urine collected the day before the measurements. Proteinuria was measured in 24-hour urine collections using routine laboratory techniques.
Renal function measurements
GFR measurements were performed using 125I-Iothalamate and 131I-hippurate infusion as
previously described9: Measurements were performed in a quiet room, with the participant
in semi-supine position. After drawing a blood sample, 125I-Iothalamate and 131I-hippurate
infusions was started (0.04 mL/kg containing 0.04 MBq and 0.03 MBq respectively). At 08.00 hour 0.6 MBq of 125I-Iothalamate was administered, followed by continuous infusion
of 12 mL/h. After a two-hour stabilization period, baseline measurements were performed in a steady state of plasma tracer levels. Clearances were calculated as (U*V)/P and (I*V)/P, where U*V represents the urinary excretion, I*V represents the infusion rate of the tracer and P represents the plasma tracer concentration per clearance period. We calculated the mGFR from clearance levels of these tracers. We corrected for voiding errors by multiplying the urinary 125I-Iothalamate clearances with the ratio of plasma and urinary 131I-hippurate
2
eGFR calculations
We used the abbreviated four-variable MDRD study equation, repressed for standardized serum creatinine samples11. The CKD-EPI equation (CKD-EPI collaboration) was calculated
gender specific and stratified by creatinine levels5. The Cockcroft-Gault formula was also
calculated12. The mGFR and the eGFR
CG were normalized for body surface area (BSA)
according to DuBois & DuBois13.
Figure 1. Comparison of pre-donation eGFR with pre- and post-donation mGFR
Deming regression plots of pre-donation eGFRCKD-EPI with measured GFR (A) pre-donation, at (B) 3
months, (C) 5 years and (D) 10 years post-donation.
Statistical analysis
Data are reported as mean (standard deviation) for normally distributed variables and median [interquartile range, IQR] for skewed data. Binary variables are shown as “number (%)”. GFR data are reported as absolute values (mL/min) and normalized for body surface area
(BSA; mL/min/1.73m2). We tested accuracy (defined as mean bias) and precision (defined as the IQR of the bias) per time-point. Ordinary least-squares and Deming regression analysis were used to assess the relationship between the different eGFR equations and post-donation mGFR. Wilcoxon matched pairs test was used to test bias differences. The performance of the different eGFR formulas to predict a post-donation mGFR <60 mL/ min/1.73m2 was measured by calculating positive predictive values (PPV) and negative
predictive values (NPV; Supplementary Table S1). We then calculated pre-donation eGFR cut-offs for prediction of fixed post-donation single-kidney mGFR thresholds of 40, 45, 50, 55 and 60 mL/min/1.73m2 using a 95% prediction interval (Figure 2). Similarly, we calculated
cut-offs for the 24h urine creatinine clearance. Statistical analyses were performed by SPSS version 22 for Windows (IBM, Armonk, NY), R version 3.0.1 (CRAN, Vienna, Austria), and Graphpad Prism 6 for Windows (Graphpad, San Diego, CA). P-values of <0.05 were considered statistically significant.
Figure 2. Pre-donation eGFR and post-donation mGFR
Scatter-dot plot of pre-donation (A) eGFRCKD-EPI, (B) eGFRMDRD, (C) eGFRCG/BSA, (D) creatinine clearance,
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Results
Patient characteristics
We included 873 living kidney donors. Mean age was 53±12 years, 48% were male. Mean pre-donation mGFR/BSA was 102±16 mL/min/1.73m2, and mean post-donation (2-3
months after UNx) mGFR/BSA was 65±12 mL/min/1.73m2. In 322 donors with available
five-year follow-up data, mean mGFR/BSA was 103±16 mL/min/1.73m2 pre-donation,
66±12 mL/min/1.73m2 2-3 months post-donation and 69±11 mL/min/1.73m2 at five years
post-donation. In 107 donors with 10-year follow-up, mean mGFR/BSA was 104±15 mL/ min/1.73m2 pre-donation, 69±13 mL/min/1.73m2 post-donation, 72±9 mL/min/1.73m2 at 5
years and 69±13 mL/min/1.73m2 at 10 years post-donation. On average, these donors had
a limited GFR loss between 5 and 10 years after transplantation (-0.7±1.8 mL/min/1.73m2/
year). Pre- and post-donation (short- and long-term) characteristics are shown in Table 1.
Table 1. Characteristics of living donors
Variable Pre-donation Post-donation
3 months 5 years 10 years
Number 873 873 322 107 Age, years 52.9 (11.8) 52.4 (11.7) 56.9 (10.0) 60.3 (9.1) Sex, N (% male) 48 48 48 45 Weight, kg 79.5 (13.7) 78.9 (13.0) 82.2 (14.4) 81.4 (15.4) Height, cm 174.8 (9.4) 174.5 (9.5) 173.8 (9.4) 172.4 (8.8) BMI, kg/m2 25.9 (3.6) 25.9 (3.4) 27.2 (3.9) 27.3 (4.2) BSA, m2 1.94 (0.20) 1.94 (0.19) 2.0 (0.2) 1.94 (0.21) mGFR, mL/min 114.2 (22.3) 73.5 (16.7) 78.4 (16.0) 77.2 (16.3) mGFR/BSA, mL/min/1.73m2 101.6 (16.3) 64.6 (11.8) 69.0 (11.4) 68.7 (12.4)
eGFRCKD-EPI, mL/min/1.73m2 87.6 (13.8) 57.7 (11.8) 64.4 (13.3) 64.1 (12.8)
eGFRMDRD, mL/min/1.73m2 85.8 (15.6) 56.2 (10.4) 63.1 (11.7) 63.1 (11.6)
eGFRCG/BSA, mL/min/1.73m2 92 (19) 63 (13) 70 (16) 68 (14)
Creatinine clearance, mL/min 132.5 (61.2) 80.3 (28.9) 76.8 (53.3) 85.9 (24.5) Systolic blood pressure,
mmHg
126.3 (13.1) 124.1 (13.4) 127.4 (13.7) 130.1 (15.7) Diastolic blood pressure, mmHg 75.9 (8.6) 76.4 (18.1) 76.7 (8.8) 77.5 (9.4) Proteinuria, g/24 hour 0.00 [0.00;0.20] 0.10 [0.00;0.20] 0.00 [0.00;0.20] 0.00 [0.00;0.20] Serum creatinine, µmol/L 78.1 (13.9) 112.4 (21.0) 100.1 (19.0) 94.8 (18.9) BSA, Body Surface Area; mGFR, measured Glomerular Filtration Rate; eGFR, estimated Glomerular Filtration Rate
Cross-sectional analyses
Both before and after donation all eGFR formulas showed an underestimation of mGFR (Table 2). The eGFRCKD-EPI had the highest accuracy and precision in prediction mGFR
Table 2. Crossectional analysis of eGFR and mGFR bias
eGFR bias in cross-sectional analysis
Variable Pre-donation mGFR /BSA (n=873) Post-donation mGFR /BSA (n=873) 5 year mGFR /BSA (n=322) 10 year mGFR /BSA (n=107) Mean (SD) IQR Mean (SD) IQR Mean (SD) IQR Mean (SD) IQR eGFR CKD-EPI -13.9 (15.3) [-23.1;4.2 ] -7.2 (10.3) [-13.0;-1.1] -5.2 (9.8) [-12.8;1.1] -5.3 (1 1.8) [-13.1;1.7] eGFR MDRD -28.5 (21.1) [-41.3;-15.1] -16.5 (13.3) [-24.0;-7.5] -15.8 (13) [-24.9;-6.8] -12.8 (15.4) [-23.0;-4.1] eGFR CG/BSA -22.2 (19.9) [-34.1;-10.7] -9.1 (12.0) [-16.2;-1.7] -9.5 (12.49) [-17.7;-1.27] -8.6 (12.0) [-17.0;1.1] CrCl 22.7 (39.5) [1.59;37.9] 16.0 (27.2) [4.0;26.0] 7.4 (31.9) [-2.8;26.8] 15.6 (23.9) [-0.99;25.7]
BSA, Body Surface
Area; mGFR, measured Glomerular Filtration Rate; eGFR, estimated Glomerular Filtration Rate; CKD-EPI, CKD-EPI formula; MDRD, MD
RD Study
2
(pre-donation bias -14±15, IQR [-23.1;-4.2], post-donation bias -7±10, IQR [-13.0;-1.1]). eGFRCKD-EPI also had the highest association with pre-donation mGFR (St. β 0.57, p<0.001, Table 2). The creatinine clearance, correctly measured in 627 donors, had a reasonable bias, but was very imprecise (pre-donation bias 14±15, IQR [4.2; 23.1], post-donation bias 16±27, IQR [4.0;26.0]).
Performance of pre-donation eGFR in predicting post-donation mGFR
All pre-donation eGFR formulas were associated with post-donation mGFR (Table 3). The pre-donation eGFRCG/BSA has the strongest association with post-donation mGFR (St. β 0.51, p<0.001), whereas the eGFRMDRD had the poorest association (St. β 0.41, p<0.001). The eGFRCG/BSA also had the strongest association with 5-year mGFR (St. β 0.45, p<0.001), while eGFRCKD-EPI had the strongest association with 10-year mGFR (St. β 0.41, p<0.001, Table 3). In Figure 1, deming regression plots are shown of the pre-donation eGFRCKD-EPI/ CrCl with post-donation mGFR. Deming regression plots for eGFRMDRD and eGFRCG/BSA are shown in supplementary figure S1.
Table 3. Univariate linear regression analyses of pre-donation eGFR on pre- and post-donation mGFR
Association of pre-donation eGFR with pre- and post-donation mGFR Pre-donation
Variables Pre-donation mGFR(n=873) /BSA Post-donation mGFRBSA (n=873) / 5 year mGFR(n=322) /BSA 10 year mGFR(n=107) /BSA St. β P R2 St. β P R2 St. β P R2 St. β P R2
eGFRCKD-EPI 0.48 <0.001 0.23 0.48 <0.001 0.23 0.42 <0.001 0.17 0.41 <0.001 0.16 eGFRMDRD 0.41 <0.001 0.17 0.41 <0.001 0.17 0.33 <0.001 0.11 0.33 <0.001 0.10
eGFRCG/BSA 0.51 <0.001 0.26 0.51 <0.001 0.26 0.45 <0.001 0.20 0.39 <0.001 0.14 CrCl 0.39 <0.001 0.15 0.35 <0.001 0.12 0.33 <0.001 0.11 0.23 0.15 0.05 BSA, Body Surface Area; mGFR, measured Glomerular Filtration Rate; eGFR, estimated Glomerular Filtration Rate; CKD-EPI, CKD-EPI formula; MDRD, MDRD Study formula; CG, Cockcroft-Gault formula;CrCl, Creatinine Clearance
A pre-donation eGFRCKD-EPI of 94 mL/min/1.73m2 (present in 33% of donors) predicts a
post-donation mGFR >50 mL/min/1.73m2 with a 95% probability, meaning that an eGFR CKD-EPI
above 94 mL/min/1.73m2 is sufficient to achieve a post-donation mGFR of 50 mL/min/1.73m2
with 95% probability (Table 4). For pre-donation eGFRCG/BSA this threshold was 99 mL/ min/1.73m2 and for eGFR
MDRD 97 mL/min/1.73m2. For the creatinine clearance the threshold
was 158 mL/min. Stricter- and more liberal eGFR cut-offs are shown in table 4. The majority of donors do not meet the eGFR cut-offs. According to our model, a confirmatory test can be avoided in approximately 7-33% of the prospective donor population, depending on their
Figure 3. Flow-chart of living donor selection
An algorithm for selecting living kidney donors. Clinicians should first determine what post-donation single-kidney GFR is required for a prospective living kidney donor. This is an individual decision and should be based on donor risk factors (age, ethnicity, co-morbidities). Donors with an eGFR below cut-off should undergo confirmatory testing. Based on current literature, mGFR is advised as confirmatory test. Donors with an eGFR above the cut-off or with an mGFR above the individualized cut-off and no relevant contra-indications for donation should be accepted.
required post-donation single-kidney GFR, which is determined using a donors age and other risk factors (Table 4; Figure 3).
Candidate for
living dona�on
post-Determina�on of required dona�on GFR eGFR (CKD-EPI or CG) ( Confirmatory test mGFR) Below Cut-offMedical and pychological screening Above Cut-off -off Above Cut-off
Decline
Accept
-Contra indica�ons? No Yes Below Cut-off mGFR cut2
Table 4. Pre-donation eGFR cut-off values to archieve fixed post-donation mGFR thresholds
Post-donation
threshold1 Pre-donation test cut-off 2 mGFR/BSA mGFR/ BSA eGFR CKD-EPI % donors eGFR MDRD % donors eGFR CG/BSA % donors CrCl % donors 40 80 69 91% 65 93% 67 95% N/A N/A 45 91 82 66% 81 59% 83 65% 102 71% 50 101 94 33% 97 21% 99 31% 158 16% 55 110 107 7% 113 6% 116 11% 215 3% 60 120 120 1% 128 1% 131 4% 271 1%
BSA, Body Surface Area; mGFR, measured Glomerular Filtration Rate; eGFR, estimated Glomerular Filtration Rate; CKD-EPI, CKD-EPI formula; MDRD, MDRD Study formula; CG, Cockcroft-Gault formula;CrCl, Creatinine Clearance
1 Post-donation single-kidney mGFR
2 to have post-donation mGFR with 95% predictid probability
Discussion
In this study, we provide pre-donation eGFR cut-off values to select donors with a high probability of having sufficient single-kidney renal function post-donation. Donors with a pre-donation eGFR above these cut-offs should be considered safe and do not require more precise measured GFR (mGFR or true GFR) measurement. Since only 7-33% of donors had eGFR values above these cut-offs, measured GFR is still warranted as a confirmatory test in the majority of donor candidates.
We show that eGFRCKD-EPI performs better in prediction of mGFR than eGFRMDRD, eGFRCG/
BSA and the creatinine clearance. Also we show that eGFRMDRD performs considerably poorer
in predicting post-donation renal function than the other formulas. This may be explained by the good pre-donation kidney function in this cohort of living donors, where the MDRD formula is known to have a poor performance in higher kidney function14.
Previous studies have determined possible cut-off values for eGFR to accept donors without confirmatory tests (e.g. mGFR)6,7, but these values were based on the predictive capacity
of eGFR on pre-donation mGFR, or even on eGFRcr-cys in the general population, while our study provides eGFR cut-offs for post-donation mGFR, in a single-kidney state.
While our study provides guidance for GFR cut-offs for donor selection, it should be noted that this strategy does not fully take long-term benign hyperfiltration and de-novo kidney disease occurrence into account. Hyperfiltration can cause GFR to increase up to 10 years post-donation and donor chronic kidney disease (CKD) develops later after donation and
cannot be predicted at young age15–18. Clinicians should take these factors into account
when determining what single-kidney GFR a donor should have post-donation. Also donor comorbidities, CKD and other factors relevant for the donation-attributable risk should be taken into account4,19–23. Based on our data, we propose an algorithm for selecting living
kidney donors that encompasses both mGFR and other risk factors (Figure 3). The first step in this algorithm is to determine what post-donation GFR is required for a prospective living kidney donor. This is an individual decision and should be based on donor risk factors (age, ethnicity, comorbidities)4,19–23. Donors with an eGFR above this cut-off that do not have other
contra-indications for donation, can be accepted without confirmatory GFR testing.
The algorithm suggests using a confirmatory test if eGFR is below the cut-off, in line with current living donor guidelines4. Based on the current state of literature and living donor
guidelines mGFR is best used as confirmatory test24, but it is expensive, laborious and
may vary dependent on the method used25. Creatinine clearance may be a reasonable
alternative: Although 24-hour urine collection is hampered by sampling errors leading to a poor precision, performing repeated collections may increase its precision and make it a viable confirmatory test26. eGFR
CysC has also been proposed as a confirmatory test, but is
considerably less accurate in most cases27,28. Further research is necessary to find the best
(combination of) tests for confirmation of renal function if eGFR is below the threshold. By implementing this algorithm in the selection of living kidney donors, the living donor pool can be extended in centers that do not have mGFR available24.
Strengths of this study include the extensive renal hemodynamic measurements with continuous infusion of 1.25iothalamate and the longitudinal design. Limitations of this study
are that our cohort consists almost exclusively of Caucasian. Also, long-term post-donation follow-up was only available in a subgroup of donors. Another limitation of this study is the low number of very young (< 30 years old) and very old donors (> 75 years old), reducing the usability of the calculated values in these groups. Also the selection of older donors in our center was very strict, which is reflected in a large proportion of donors having an adequate post-donation mGFR. Therefore, we are unable to make predictions on donors who should be rejected without the use of a confirmatory test.
In conclusion, we used a large cohort of living kidney donors with mGFR measurements before and at three time points after donation to provide cut-off values for pre-donation eGFR to select donors with adequate post-donation mGFR. These cut-offs may be used for donor guidelines to select donors that do not require mGFR confirmation of eGFR. We propose a selection algorithm incorporating these thresholds to further improve donor safety. Donors with an eGFR below the cut-off should undergo additional renal function evaluation, preferably by mGFR, while donors with eGFR above the cut-off can be safely accepted without additional renal function measurement.
2
Acknowledgments
Dr. De Borst is supported by a Veni grant from the Dutch Organization for Scientific Research (grant no 016.146.014). The authors would like to thank all living donors that participated in this study.
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Supplementary data
Table S1. Positive and negative predictive values of eGFR equations and the creatinine clearance to detect a post-donation mGFR < 60 mL/min/1.73m2
Predictive Values for post-donation mGFR Predonation GFR cut-off 3 months (N=873) 5 years (N=322) 10 years (N=108) Method Value PPV NPV PPV NPV PPV NPV CKD-EPI 99 42.9 92.1 30.5 98.2 22.3 84.6 MDRD 102 39.7 89.4 27.0 88.9 22.0 85.7 CG/BSA 108 41.9 90.7 29.3 94.3 21.5 78.6 CrCl 164 40.6 85.6 30.5 89.8 22.0 73.3 mGFR 106 53.2 95.2 39.6 97.5 30.5 89.6
BSA, Body Surface Area; mGFR, measured Glomerular Filtration Rate; eGFR, estimated Glomerular Filtration Rate; CKD-EPI, CKD-EPI formula; MDRD, MDRD Study formula; CG, Cockcroft-Gault formula;CrCl, Creatinine Clearance; PPV,positive predictive value; NPV, negative predictive value
Figure S1. Comparison of pre-donation eGFR/creatinine clearance with pre- and post-donation mGFR
Deming regression analysis of pre-donation eGFRMDRD (A), eGFRCG/BSA (B) and the creatinine clearance
(C) with mGFR at different time-points. (1) shows the association with pre-donation mGFR, (2) with mGFR 3 months post-donation, (3) with mGFR five years post-donation and (4) with mGFR 10 years post-donation.
