End-stage kidney disease (ESKD) is an important and expanding health problem worldwide.1 Increasing prevalence of diabetes and hypertension, combined with population aging, is predicted to result in a sharp increase of ESKD within decades, especially in developing countries.1 ESKD is associated with increased mortality, reduced quality of life, and high cost.2-6 In 2016, in France, the survival rate for 5 years post-ESKD onset was 50% compared with a life expectancy of 20 years for age-matched individuals.7 Furthermore, between 1990 and 2010, the age-standardized death rate from chronic kidney disease (CKD) increased from 9.6/100 000 in 1990 to 11.1/100 000 in 2010.8 Currently, the treatment of choice for ESKD is kidney transplantation (KTx) because it confers improved quality of life and survival and is less costly compared with dialysis.2,3,5,9,10
At present, KTx is not reaching its full potential. The availability of organs is far outstripped by the demand for organs. In 2016, in France, 11 936 ESKD patients were active on the KTx waitlist, but only 3615 KTxs were performed.7 In the Eurotransplant network (Austria, Belgium, Croatia, Germany, Hungary, The Netherlands, Luxembourg, and Slovenia), 11 105 patients were on active waitlists in 2017, while 4419 KTx were performed.11 In the United States, in 2016, the kidney transplant waiting list had 51 238 active candidates, while 20 161 KTxs were performed.12
A multipronged approach is required to address this imbalance.13 One important component is increasing living donation that has many advantages over deceased donation.14,15 Various initiatives have been undertaken to accomplish this, such as the institution of kidney paired donation programs, the expansion of the donor pool by accepting medically complex candidates with advanced age, controlled hypertension, impaired glucose tolerance, or mild-moderate obesity.13,14,16,17 Efficiencies in donor workup with expedited processes have also been recommended to address the long donor evaluation time, an identified barrier to living donation.13,18
While there are numerous accepted medical reasons to increase living donations, donors must be carefully evaluated to enable the appropriate selection of candidates with acceptable risks and avoid the inappropriate rejection of suitable candidates.19,20 The number of prior kidney donors with ESKD listed in the United States on kidney transplant waitlists is increasing yearly (45 in 2014 versus 6 in 2004) for a total of 441 between 1996 and 2015.21 Although the 15-year incidence of ESKD postdonation is low (31 of 10 000 donors over first 15 y); this represents an 8-fold increased incidence of ESKD in kidney donors compared to healthy individuals in the United States who have not donated.19 A similar Norwegian study showed an 11-fold increase.20 Several factors have been proposed to explain this, including genetic and environmental factors and donor selection practices that fail to identify donors at increased risk of ESKD.21,22 The trend toward accepting medically complex donors with comorbidities, at higher risk of ESKD regardless of donation, makes donor evaluation even more critical.14
This review will provide an overview of the relevance of glomerular filtration rate (GFR) assessment for living kidney donor candidates and the methods to evaluate GFR in healthy individuals and will compare and contrast the different available donor assessment guidelines as they pertain to GFR evaluation and minimally acceptable GFR thresholds. Finally, we discuss existing knowledge gaps and suggest an approach to kidney donor evaluation that considers evidence available to date with the goals to maximize appropriate donation and minimize inappropriate donation.
RELEVANCE OF GFR EVALUATION FOR LIVING KIDNEY DONOR CANDIDATES
Evaluation of the GFR of living kidney donors is a cornerstone of predonation screening because donors will be initially left postdonation with 50% of their original renal mass. By virtue of compensatory mechanisms of the remaining kidney, donor GFR 1-year postdonation is on average 70% of its predonation value.23 Regardless of the ESKD cause, lower baseline GFR has been shown to be associated with an increased ESKD risk in both the population of potential donors who never donated22 and the population of donors.24 Furthermore, in a recent focus group study, postdonation kidney function was ranked the most important outcome by previous kidney donors.25 Despite strong evidence supporting the importance of predonation renal function evaluation, how and when this should be conducted is still debated, and the values of acceptable predonation GFR are variable across programs and guidelines.26-28
AN OVERVIEW Of GFR ASSESSMENT IN HEALTHY INDIVIDUALS
Historically, estimating GFR was performed by measuring creatinine (Cr) clearance using 24-hour urine collections.29 These overestimate GFRs due to Cr secretions being fraught with collection issues and are not recommended.30 GFR is now most frequently assessed using equations that estimate GFR (estimated GFR [eGFR]) using serum concentrations of endogenous markers that undergo glomerular filtration.31 These equations incorporate demographic variables to account for some of the non-GFR determinants of marker concentration. The most common marker is Cr, and the recommended equation is the CKD-epidemiology (CKD-EPI) equation (eGFR with the CKD-EPI equation based on Cr [eGFREPI-Cr]).32 In recent years, additional equations have been proposed which also include novel endogenous markers such as cystatin C (CysC),33 beta-trace protein (BTP), and beta 2 microglobulin (B2M).34,35 The multimarker eGFR with the CKD-EPI equation based on CysC and Cr (eGFREPI-CysC/Cr) equation has now been incorporated into the Kidney Disease Improving Global Outcomes Group (KDIGO) CKD guidelines as a mean to confirm an unexpected low eGFREPI-Cr or in circumstances when eGFREPI-Cr is known to be less accurate.30 The performance of the eGFR is typically compared with the gold standard measured GFR by its bias (difference from GFR measurement [mGFR]), precision (standard deviation of the mean bias or interquartile range of median bias), and accuracy (percent of estimates within 10% or 30% of the mGFR) that incorporates both bias and precision.30 However, measuring GFR with exogenous markers such as inulin, iohexol, and technetium-99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA) may be costly, difficult, and typically used only when an exact GFR level is required.30 Most mGFR and estimation methodology studies focus on GFR assessment in the setting of low GFR. Little is known about GFR assessment in individuals in good health as are living kidney donors. There are biologic and analytic factors that require special considerations in this population.
Measurement of GFR with exogenous tracers (mGFR) is the gold standard to evaluate kidney function. Unfortunately, high cost, lack of availability, and cumbersomeness30 limit the availability of mGFR for routine clinical use. Measured GFR is performed by calculating the plasma or urinary clearance of an exogenous marker.29 The historical gold standard is urinary inulin clearance29 and is performed by inulin loading then infusion, with collection of timed plasma and urine samples. However, inulin and its assay are expensive and finicky. Inulin is only produced in Austria, is not available at all in the United States,36 and is performed in few centers worldwide. Recently, 2 serious adverse events in France motivated its temporary withdrawal from the market.37
Many different tracers and protocols are used as alternatives to the classic urinary inulin clearance. However, the availability of tracers varies greatly from one country to another, hence limiting the development of worldwide recommendations with a unique tracer. For example, in Europe, 51Cr-ethylenediamine tetraacetic acid can be used, but it is not available in the United States. 51Cr-ethylenediamine tetraacetic acid is also quite expensive and requires dedicated facility for radioactive elements. Inversely, iothalamate commonly used in the United States is not easily available in Europe. 99mTc-DTPA is used almost exclusively in Canada, but in recent years, there have been significant difficulties with the supply of 99mTc-DTPA due to reactor malfunctioning and intermittent reactor shutdowns.38 Iohexol is a low osmolar contrast agent widely used intravenously in radiologic procedures and is freely filtered at the glomerulus. Iohexol has many advantages in that it is inexpensive, available worldwide, and safe. Iohexol is the most common GFR tracer in Europe and routinely used in clinical trials.39 Iohexol is assayed using high-performance liquid chromatography with or without tandem mass spectrometry.39
Plasma methods that sample plasma at varying time points after tracer injection (ie, do not require urine collections) are already popular for obvious logistical reasons.40,41 The accuracy of plasma methods depends on the number and timing of samples and GFR level of the study subject.42-44 In advanced CKD, delayed sampling (ie, >10 h) has been recommended to avoid overestimating GFR due to delayed clearance and tracer diffusion into otherwise inaccessible compartments.43
The ideal plasma sampling strategy in patients without CKD is not known. Studies comparing mGFR methods have almost exclusively been conducted in individuals with CKD. Only one study has focused on patients without CKD.45 Plasma iohexol clearance was measured in 20 healthy subjects (median GFR of 117 mL/min/1.73 m2). Plasma was sampled 5× between 150 and 240 min. The GFR obtained using 5 samples (150 to 240 min) and using 4 samples (180 to 240 min) were compared with renal inulin clearance.46 The 5-sample GFR with the earlier 150-min sample was much lower and closer to the renal inulin GFR than the later 180-minute 4-sample GFR. However, even with the earlier 150-minute sample, the inulin GFR was underestimated by 13 mL/min/1.73 m2, which raises the question as to whether an even earlier initial sample is required in patients with high GFR. A deficiency of the study was that the inulin GFR and iohexol GFRs were not performed simultaneously. The timing of the last sample may also be important. In that study, the last sample was taken at 240 minutes when serum marker concentrations were likely very low from rapid renal excretion.46 Due to the inverse relationship between marker concentration and GFR, large changes in calculated GFR occur with small changes in analyte concentration when these are low.47 The analytical error in iohexol measurement could have a significant impact on GFR determination with later sampling, similar to what is observed with eGFR-Cr when Cr concentrations are low.47 Protocols with early sampling have not been done. Due to the limitations of mGFR, several alternatives are available.
Estimation of GFR with Creatinine
Many non–GFR-related factors influence Cr levels, such as muscle mass, diet, hepatic function, and tubular secretion.48 The incorporation of age, race, and gender into the eGFR-Cr does not completely adjust for the contribution of all of these factors, resulting in equation imprecision and inaccuracy.49 This is particularly true when the individual differs in terms of the non–GFR-Cr determinants from the equation development population.49 Cr generation may be much higher in healthy donors compared with those with CKD due to higher protein diets and muscle mass while Cr secretion may be lower.49 None of the common equations were developed primarily in healthy populations.30
The performance of eGFREPI-Cr in living donors has been examined. In one study of actual donors (n = 253), predonation eGFREPI-Cr underestimated mGFR by a median of 14 mL/min/1.73 m2.50 Precision was poor with a wide interquartile range of 18 mL/min/1.73 m2, while the percent of estimates within 30% was 89%. The probability of having an mGFR <80 mL/min/1.73 m2 when the eGFR <80 mL/min/1.73 m2 was only 14%, indicating that 86% of those who would be rejected based on an eGFR <80 mL/min/1.73 m2 would be suitable donors using mGFR. In the same study, the incidence of predonation eGFR <80 mL/min/1.73 m2 was high, such that 42% would have been rejected had eGFREPI-Cr been used to decide on their suitability.50 In comparison, only 0.04% of donors had mGFR <80 mL/min/1.73 m2. The largest study in potential kidney donors (n = 583) had similar findings.51 On average, eGFREPI-Cr underestimated mGFR by 10 mL/min/1.73 m2. Among subjects with mGFR <80 mL/min/1.73 m2, 39% had eGFR >80 mL/min/1.73 m2, so would be wrongly accepted as donors. Among subjects with mGFR >80 mL/min/1.73 m2, 24% had an eGFR <80 mL/min/1.73 m2 and would be wrongly excluded. They do not present numbers by eGFR. Thus, the use of eGFR-Cr for donor determination results in both rejection of suitable candidates with a falsely low eGFR-Cr and acceptance of unsuitable candidates with a falsely high eGFR-Cr.
Estimation of GFR with CysC
CysC is less affected by muscle mass, gender, race, and diet than serum Cr, and several equations incorporating CysC alone or with Cr have been proposed.52,53 In large CKD populations, eGFREPI-CysC/Cr has been shown to have improved accuracy over eGFREPI-Cr.33,54 The accuracy of eGFREPI-CysC/Cr in healthy populations has not been well established. One study (n = 147 potential donors) showed that the combined equation was much less biased compared with mGFR than the eGFREPI-Cr alone (5 versus 14 mL/min/1.73 m2).49 Precision, accuracy, sensitivity, or specificity at different GFR thresholds were not examined. Of note, the eGFREPI-CysC can be confounded by the “shrunken pore syndrome” that is defined by an eGFREPI-CysC < 60% of eGFREPI-Cr.55 Interestingly, the concept of shrunken pores was proposed to explain the observed eGFREPI-CysC decrease in pregnant women in the third trimester, while eGFREPI-Cr and mGFR were unchanged. Later, the shrunken pore syndrome was associated with increased mortality in patients with coronary surgery56 and declined right ventricular systolic function.57 The clinical relevance of shrunken pore syndrome among living kidney donors has never been evaluated. Importantly, the 2017 KDIGO living kidney donor guidelines include validation of the novel equations in the donor evaluation setting as a research priority.27
Estimation of GFR with BTP or B2M
BTP and B2M are two low molecular weight proteins that are also showing some promise as endogenous markers of GFR.58-60 The CKD-EPI consortium developed eGFR-BTP/B2M and eGFR-B2M equations in a large CKD population.61 These do not, however, appear to offer any incremental advantage over eGFREPI-CysC/Cr in CKD, transplant recipients, or the elderly,61-63 and how they perform in good health is unknown.
Predicting mGFR Based on eGFR
A Web-based tool has been developed to determine probabilities for various relevant mGFR thresholds (http://ckdepi.org/equations/donor-candidate-gfr-calculator/). The calculator incorporates donor characteristics (age, sex, and race) and donor Cr ± CysC. The application calculates the probability to have an mGFR <60 and 70 mL/min/1.73 m2 and >80 and 90 mL/min/1.73 m2. Each center can then theoretically use these probabilities to decide whether GFR needs to be measured or not.64 Using donor registry data and the tool, the authors determined that 53% of recent donors had a predonation eGFR high enough to ensure >95% probability that predonation “mGFR” was >90 mL/min/1.73 m2 and suggest that a significant population of donors do not require mGFR to confirm GFR suitability.
When studied in a French population of living kidney donors with measured GFRs (n = 311 for development cohort and n = 354 for the validation cohort), we found that to obtain a 100% chance of having an mGFR >80 mL/min/1.73 m2, it is the predicted probability of having an mGFR >90 mL/min/1.73 m2 (and not 80) that had to be >98%.65 Additionally, we observed that the eGFREPI-Cr had to be >104 mL/min/1.73 m2 to guarantee that all donors have an mGFR >80 mL/min/1.73 m2.65 Overall, the Web-based calculator detected all potential donors with an mGFR <80 mL/min/1.73 m2 (ie, is highly sensitive) but had low specificity of 32%. In other words, 68% of the potential donors with an mGFR predicted to be <80 mL/min/1.73 m2 in fact have an mGFR <80 mL/min/1.73 m2.
Some elements of the study design of the Web tool are of concern. Pretest probabilities for mGFR thresholds were derived from the prevalence of eGFREPI-CysC/Cr thresholds and not from mGFR. Importantly, the derivation population was composed largely of patients with CKD. The relationship between eGFR and mGFR is quite different in healthy people compared with CKD populations, and thus the likelihood ratio may not reflect those of the target population.49 Importantly, this calculator can only be used for 4 fixed GFR thresholds, including the decision thresholds recommended by the KDIGO guidelines (60 and 90 mL/min/1.73 m2). It may be that other thresholds become important as evidence emerges about risk, GFR, and donor age.66 Except the KDIGO guidelines that recommend fixed GFR threshold for living kidney donor screening, other guidelines recommend age-adapted thresholds,26,28,67 making the use of this calculator difficult.
GFR Assessment Protocols
Considerable heterogeneity and uncertainty exist in available guidelines for GFR assessment in potential living donors (Table 1). The 2015 Canadian Transplant Society (CTS) guidelines governing kidney paired donation recommend eGFR as a first step and then either a measured urinary Cr clearance or an mGFR.26 A similar approach is proposed by the American Organ Procurement and Transplantation Network without an explicit mention of exogenous tracer mGFR.68 The British Transplant Society (BTS), explicitly mandates mGFR.67 The 2013 European Renal Best Practice (ERBP) guidelines state that eGFR-Cr should be used but “when there is doubt regarding the accuracy of GFR from estimation methods, a direct measurement of GFR should be taken by exogenous clearance methods.”28 The 2017 guidelines from the international KDIGO group explicitly acknowledge the lack of evidence stating “the search parameters did not identify evidence pertinent to the recommendations…and therefore the recommendations are Not Graded.”27 KDIGO recommends starting with an eGFR-Cr with confirmation of this with an mGFR. If mGFR is not available, then Cr clearance, eGFREPI-Cr/CysC, or repeat eGFREPI-Cr are also acceptable.27 None of the guidelines provide any specifications of mGFR protocols (urinary versus plasma and sampling strategy) or acknowledge that there are differences between them.
Acceptable GFR cutoffs vary between guidelines (Figure 1) and those proposed are not method dependent and therefore do not account for the significant average underestimation of mGFR by eGFR in potential donors. The KDIGO guidelines acknowledge the lack of data to support method-specific cutoffs.27 Currently, the GFR cutoffs selected by the KDIGO committee are 60 mL/min/1.73 m2 or below to routinely decline donation and 90 mL/min/1.73 m2 to routinely accept donation. In between, eligibility should be based on the predicted ESKD by online calculators that incorporate age, gender, race, eGFR, systolic blood pressure, hypertension medication, body mass index, presence of non–insulin-dependent diabetes, urine albumin to Cr, and smoking history.22 That calculator, however, provides an ESKD risk in the absence of donation because it was not developed in among donors.
Since GFR physiologically declines with aging, the BTS 2018,67 ERPB,28 and the CTS guidelines26 recommend the use of age-adapted GFR thresholds. The ERBP guidelines are based on the BTS 2011 guidelines and recommend that baseline GFR should be high enough, so that a donor will have a GFR >37.5 mL/min/1.73 m2 at 80 years of age. The new BTS 2018 suggests that baseline GFR should be >−2 standard deviation of the mean GFR observed in potential living kidney donors67 and adds a new threshold of 90 mL/min/1.73 m2 for younger donors (age < 30 y). The CTS guidelines recommend a GFR ≥90 mL/min/1.73 m2 for donors of age from 18 to 30 years, a GFR ≥85 mL/min/1.73 m2 for donors of age from 31 to 40 years, a GFR ≥80 mL/min/1.73 m2 for donors of age from 41 to 65 years, and a GFR ≥75 mL/min/1.73 m2 for donors of age >65 years.26 Overlooking this physiological process and having age-independent fixed cutoff could result in restricting donation for older but otherwise healthy potential donors while being potentially too liberal for younger potential donors.66
We simulated the impact of those various guidelines in a cohort of 2007 French living kidney donors who underwent mGFR with an exogenous tracer. For each guideline, the percentage of eligible donors is summarized in Table 2 and presented in Figure 2.
Overall, the KDIGO guidelines yield the fewest number of donors unambiguously eligible to donate and the greatest number ineligible to donate. That is not surprising since these are the only guidelines that do not use an age-independent threshold to define eligibility for donation.
Timing of Kidney Function Evaluation/Discordance of Results
Screening of living donor candidates is often long and costly,3 and the first steps usually consist of simple, easily available tests to rule out major contraindications to donation. As discussed above, most guidelines require >1 kidney function measure (two-stage testing; Table 1). However, the timing of the interpretation of the results vary somewhat between them. KDIGO, ERBP, CTS, and Organ Procurement and Transplantation Network examine the results of the eGFR and the confirmatory test concurrenty. The new BTS guidelines have a sequential strategy with, as a first step, the eGFR, and if the eGFR is <45 mL/min/1.73 m2 (an unequivocally low GFR, regardless of age and sex which is incompatible with donation66), then the evaluation process is halted and the individual is referred to nephrology for CKD diagnosis. If eGFR is >45 mL/min/1.73 m2, then the measured GFR confirmatory test is ordered. The different screening strategies are summarized in Figure 2.
None of the guidelines address what the clinician should do when the eGFR and confirmatory tests yield discordant results and practices likely vary between centers and individual patients based on characteristics and physician/local beliefs and practices.
Suggested GFR Evaluation in Living Donor Assessment
Studies comparing eGFR to mGFR in potential donors reveal that excluding potential donors based on low eGFR will result in the rejection of suitable candidates with falsely low eGFR-Cr and acceptance of unsuitable donors with falsely high eGFR-Cr.49,50,70 One approach to address the discrepancy between eGFR and mGFR would be to have method-specific GFR thresholds. This approach, however, is complicated and does not really address the issue of what the clinician is to do when discordant results occur (after repeating). Furthermore, mGFR availability worldwide is variable, especially in developing countries where health resources are limited and where living kidney donation may be the unique source of kidney transplants. One may argue that insisting on mGFR for donor evaluation may therefore disadvantage patients with CKD in poorly resourced countries. Yet, a recent work demonstrated the feasibility of mGFR in West Africa71 suggesting that mGFR availability has probably not yet reached its full potential.
An alternate approach is to adapt eGFR thresholds to the best locally available technique. This would allow an eGFR-based selection to better simulate an mGFR-based selection. Development of the Web-based calculator and our complementary work validating its use among potential donors are the first initiatives to adapt eGFR thresholds to mGFR.64,65 These studies indicate that it is possible to define different eGFR thresholds for mGFR thresholds, albeit at the cost of a percentage of uncertainty as to whether the mGFR threshold is indeed surpassed. Of note, at present, different thresholds for eGFR have only been validated for a fixed mGFR threshold of 80 mL/min/1.73 m2.65 Other thresholds were not validated in an independent cohort.
In addition to age and technique-dependent GFR thresholds, the question as to whether others variables should be considered when setting for the minimum acceptable predonation GFR has not been well explored. For example, recent work by Doshi et al72 on black living kidney donors suggest that donors harboring the high-risk apolipoprotein L1 (APOL1) alleles (G1 or G2 variants) experience a faster decline of renal function after donation (1.1 versus 0.4 mL/min/ 1.73 m2/y; P = 0.02). In this article, two donors with the high-risk APOL1 allele developed ESKD 10 and 18 years after donation. Both had hypertension. One may wonder whether a higher baseline GFR would have changed the course of kidney disease or simply delayed the ESKD onset. Beyond APOL1, in a preliminary study comparing the course of GFR evolution after donation between Caucasian and African donors, we found that donors of African ancestry (without the high-risk APOL1 genotype) had a lower compensatory response after donation compared with Caucasian donors, which suggests that APOL1 does not encapsulate the entire increased ESKD risk of donors of African ancestry.73 In addition, we acknowledge that the whole kidney GFR either measured or estimated cannot assess single nephron GFR. That is probably a major concern because two individuals with similar mGFR can have different nephron numbers and different single nephron GFRs. As the nephron number is tightly linked to birth weight,74-76 it would be interesting to interpret GFR values of living donors in light of their birth weight. Thresholds dependent on sex or comorbidities could also be considered. Further data are required exploring the associations between these variables and the course of postdonation renal function.
There remain many uncertainties in GFR assessment in living kidney donation, including appropriate donor thresholds across age, gender, comorbid status, long-term donor risk, and the optimal GFR assessment strategy. GFR estimation and measurement tools have largely been conducted in CKD populations and are not necessarily valid in a healthy population of living kidney donor candidates. Furthermore, GFR evaluative studies have largely been conducted in approved donors and not in those initially presenting as potential candidates, which puts into question their suitability for potential donor evaluation. Donor workup guidelines are as a result vague and often opinion rather than evidence based. An approach that considers eGFR thresholds appropriately validated using mGFR with or without additional patient characteristics (gender, age, race, and comorbidities, etc.) is required. However, for this to occur, significant new knowledge addressing the uncertainties outlined above will need to be conducted.
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