EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Introduction
Glomerular filtration rate (GFR) measures how much blood is filtered by the kidneys each minute. It is the best available overall indicator of how well an individual’s kidneys function at a given moment.

Nearly a century has passed since the first report by Paul Brandt Rehberg who published “the rate of filtration and reabsorption in the human kidney” describing the calculation of GFR through the exogenous administration of creatinine.¹ Since then, many events have refined the understanding and applicability of GFR in the practice of nephrology. In 2020, the National Kidney Foundation and the American Society of Nephrology announced a joint task force to examine the inclusion of race in estimating GFR and its implications for diagnosing and managing patients with kidney disease.²

Kidney transplantation is the best possible form of kidney function replacement therapy. However, in many parts of the world, as in the Middle East, living donors are the primary source of the kidney donation pool.

The crucial step in evaluating living donor candidates is properly assessing kidney function before donation to select the best candidate while applying Primum non nocere. In the past decade, GFR selection criteria for living kidney donors have received an increasing emphasis as data have demonstrated increased risks of kidney disease after donation, including a small increase in the risk of kidney failure.³

Why do we stress elucidating this concept in the Middle East Society for Organ Transplantation (MESOT) region? First, in most countries with limited resources, living kidney donation is still the primary source of kidney donors. Second, the typical donor in this region is a young male or female individual in the productive years of their lives. So, we should be cautious not to create more misery through the process of donation.⁴

In this review, the current understanding and application of GFR-based selection criteria are described, as well as future perspectives on GFR to avoid misclassifying living kidney donor candidates.

Glomerular Filtration Rate Assessment Caveats
No consensus guidance
Most societies and the Kidney Disease Improving Global Outcomes (KDIGO) have published recommendations for living donor evaluations based on systematically collected evidence.^5,6 Unfortunately, there was no consensus on the age, GFR limit, or technique used. Notably, the British Transplantation Society 2018 recommendations suggested a GFR of 45 mL/min/1.73 m² as the lowest threshold for evaluation of the donor candidate. In addition, the society recommended a sequential approach to estimate and measure GFR that should be adjusted to a compatible age threshold to make a final decision for donation.⁷ In the KDIGO 2017 recommendations, proper pretransplant and possible posttransplant risk assessments are mandated using center-specific risk thresholds. This means long-term donor registry data, which may not be applicable in low-resource situations with no registries.

Exogenous versus endogenous markers
The gold standard for measuring GFR involves measuring plasma or urinary clearance of an exogenous marker such as inulin. However, the cumbersome nature of the procedure has restricted its use to academic settings only. Other exogenous markers like 99mTc-DPTA, 51Cr-EDTA, 125I-iothalamate, or Iohexol have pros and cons.⁸ In addition, these interpretations may be procedure dependent, such as high-performance liquid chromatography versus liquid chromatography with tandem mass spectrometry procedures.⁹

Endogenous molecules that provide an unbiased and precise evaluation of kidney function are still necessary. Both creatinine and cystatin C have their limitations. However, a combined creatinine-cystatin C equation performed better than equations based on either of these markers alone.¹⁰ Recently, d-serine, a rare enantiomer of serine and endogenous biomarker of kidney function, has been evaluated in living donor candidates. Again, combined measurement of d-serine and creatinine has the potential to serve as a measure of GFR with precision and minor biases than either alone.¹¹

Estimated, measured, or both
Creatinine clearance has been the mainstay for estimating GFR in laboratories for the past half century. The method involves a continuous intravenous infusion of the marker accompanied by repeat blood and/or urine collections at carefully timed intervals. However, despite the accuracy offered by exogenous markers, measuring their clearance is too labor intensive and time consuming for use in ambulatory settings. Therefore, the alternative is to calculate an estimated GFR (eGFR) based on the serum or plasma concentration of an endogenous marker such as creatinine or cystatin C.

The 2017 KDIGO guidelines recommended the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for the initial assessment of GFR, which was developed in 2009 to overcome the shortcomings of the 2006 Modification of Diet in Renal Disease study equation.¹² In addition, with the previous evidence that combined values for creatinine and cystatin C were better than either alone, the KDIGO 2017 guidelines suggested a mean eGFR value for combined creatinine-based and cystatin-based CKD-EPI equations.¹³ Such an approach will avoid the shortcomings of each, increasing precision and accuracy and reducing bias across the range of eGFR values.

If the initial eGFR is at the acceptable level, confirmation by measured creatinine clearance should be the next step in the donor evaluation process.

A race-neutral glomerular filtration rate
A coefficient of 1.159 as a variable was added to eGFR equations like the Modification of Diet in Renal Disease and the 2009 CKD-EPI equation for Black individuals as a result of possible evidence of increased serum creatinine concentrations compared with White patients or patients of other races. Thus, in matched White and Black patients with identical serum creatinine concentrations, age, and sex, the eGFR will be increased for Black patients as a result of this race coefficient.^14,15 This raises 2 questions about the robustness of evidence regarding increased creatinine for Black individuals, and can race be interpreted using binary variables? Answering these questions emphasizes the current state of increasing racial diversity and mixed-race populations. Furthermore, not all health care providers discuss race and ethnicity with patients during evaluations but make visual assumptions only. The net result will be limited access to transplantation and higher donor rejection.

The use of GFR biomarkers in which race is not a major GFR determinant has been suggested. For example, ?-trace protein and b2-microglobulin have stronger associations with adverse outcomes than creatinine and are less influenced by race. A panel of these 2 biomarkers plus creatinine and cystatin C was accurate for creatinine and cystatin C-based eGFR without consideration for race.¹⁶ In 2021, the National Kidney Foundation and American Society of Nephrology task force on reassessing the inclusion of race in diagnosing kidney disease recommended a unifying approach to the immediate implication of the CKD-EPI creatinine equation refit in all US laboratories.² This was evaluated by Inker and colleagues and the CKD-EPI Collaboration. They concluded that omitting race resulted in a more accurate eGFR, leading to smaller differences between Black and non-Black participants than new equations without race with either creatinine or cystatin C alone. ¹⁷

Donor age
With the increasing need for donors, older donors represented a possible valuable addition to the donor pool. Thus, kidney transplant from selected donors aged 70 years and older can succeed and should be considered, especially for older recipients.18 However, a significant hurdle for accepting such donors is the renal function and how to differentiate between renal senescence and renal disease. This implies a dynamic view of age and renal function, as age-related declines in GFR are a normal physiological process that does not preclude donation.

Indeed, accumulating data have strengthened the notion that normal kidney aging is physiologically associated with GFR decline but structurally different from kidney disease. For example, the mean fall in GFR each decade after 40 years is 6.6 mL/min/1.73 m² for men and 7.7 mL/min/1.73 m² for women. Accordingly, 40 years will be the turning point in calculating the physiological decline of GFR according to donor age.¹⁹

Gaillard and colleagues elegantly described that age-calibrated GFR might improve the efficiency of the selection process. They have defined a novel metric, the lifetime-standardized renal reserve, which combines GFR before donation and life expectancy and thus allows comparisons of the available GFR reserve between different age categories. For older and healthy candidates with low but well age-calibrated GFR, the pace of GFR decline after donation is likely too slow to lead to end-stage kidney disease over an average human lifetime. This was a multicenter retrospective analysis that has been reproduced by an Australian prospective analysis for donors enrolled in the Australian Kidney Exchange program.^20,21

According to Gaillard and associates, the threshold of GFR usually deemed acceptable for donation and for proceeding to additional donor workup has been set at 80 mL/min/1.73 m² and not 90 mL/min/1.73 m². The best example comes from the British Transplantation Society, which has adopted different age-dependent GFR thresholds varying from 80 mL/min/1.73 m² for the youngest candidates to as low as 50 mL/min/1.73m² for donors older than 80 years.⁷ This latest approach may seem physiologically sound. Furthermore, it aligns with the well-recognized relationship between age and GFR and, on the other hand, the uncertainty around the pathogenicity of age-related GFR decline.

Point of care creatinine and estimated glomerular filtration rate
A quick determination of creatinine using a point of care (POC) device would facilitate the assessment of kidney function. These are low-maintenance handheld POC devices that can measure enzymatic creatinine/eGFR directly in capillary and venous whole blood (1.2 mL), providing a result within 30 seconds. The World Health Association has developed the ASSURED criteria for evaluating POC devices, which are Affordable, Sensitive, Specific, User-friendly, Rapid and Robust, Equipment-free, and Deliverable, to end-users.²² Creatinine measured with the POC has an acceptable performance when used with the CKD-EPI equation to estimate GFR. Its ability to detect GFR of <60 mL/min/1.73 m² is not significantly different from the classical biochemical assay.²³ Creatinine values can be used for GFR screening before contrast media injection. This can be translated into an assessment of GFR in living donor candidates at low cost and within a short time before embarking on a detailed measurement of the GFR. By this, the dogma of >90 mL/min/1.73 m² or <60 mL/min/1.73 m² as cut-offs to accept or refute donation can be avoided.

Assessment of donor kidney function using body surface area-adjusted and age-adapted criteria is para-mount to ensuring donor safety. At the same time, assessing the absolute GFR of the transplanted kidney is vital from the recipient’s point of view. However, in elderly donor-recipient pairs, absolute GFR of 80 mL/min, if adequate from a donor standpoint, may still yield adequate kidney function for the recipient and better outcomes than dialysis.²⁴

All of these caveats should consider any risks after dona-tion. Therefore, risk calculators for potential donors should be modeled according to the program and regional data to calculate the proper risk for the respective donor pool.

The Possible Approach
The initial assessment would start with creatinine-based CKD-EPI. Here, a POC handheld device can be used to measure creatinine and calculate eGFR. A lower limit for GFR should be detected according to the age of < 40 or ?40 years. Then, a confirmatory measurement of the GFR would be appropriate. If the GFR is below that expected for donor age and/or the end-stage kidney disease risk calculator is above the accepted level, the donation would be declined. With the age of 40 years as a cut-off to measure lower limits of GFR normality, the DESCARTES working group of the European Renal Association suggested the following in their recent position statement on predonation assessment of the GFR: (1) a decision based on age-adapted GFR evaluation should be preferred over a decision based on a fixed GFR threshold; (2) valid and easy-to-implement reference methods to measure GFR exist, which should be systematically considered for predonation renal function evaluation; (3) eGFR is not accurate enough for unambiguous donor selection, but can be considered as part of an age-adapted evaluation in situations where reference methods are not available; and (4) life-long follow-up of the donor is mandatory irrespective of the predonation GFR value.^8,25

In conclusion, the evaluation of each living donor candidate is highly intricate. Proper assessment of kidney function is central to the evaluation process. An accurate initial eGFR should be confirmed by a measured GFR. Age-dependent and race-neutral values should be the standard. A unifying approach with a global consensus on GFR assessments and risk calculations before donation will shape the practice and avoid misclassifying living kidney donors.

Volume: 20 Issue: 8 August 2022 - Supplement - 4

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