The ongoing disparity between the numbers of patients with end-stage kidney disease waitlisted for transplantation and the availability of donor organs has compelled transplant teams to use less ideal donors. The increase in the number of deceased donors over the last decade has been driven by donation after circulatory death (DCD) donors,1 although organ utilization has not been maximized, and quality cannot be routinely optimized beyond standard cold storage preservation techniques. The untapped potential of DCD organ donors, particularly kidneys, was explored in an Australian study, which estimated that two-thirds of DCD donors were not identified,2 thought to be due to the lack of both clinical predictability and standardized criteria to establish donor suitability.
The trend in accepting DCD kidneys has also coincided with increased numbers of kidneys declined for transplantation. In a US-based study, 20% of DCD kidneys were discarded overall (with a center-dependent range of 3%–33%), and the odds ratio of discard increased with warm ischemic time.3 DCD status independently increases the risk of donor kidney discard has been validated.4 A similar pattern is seen in the United Kingdom, where discard rates of procured kidneys have more than doubled in the last decade.5 Prolonged exposure to warm ischemia in DCD donation, combined with subsequent cold ischemia, increases the risk of primary nonfunction, as well as delayed graft function and acute rejection that robustly influence graft loss.6 However, long-term (10-y) graft and recipient survival have been shown to be equivalent between DCD and donation after brain death (DBD) groups.7 This suggests transplant clinicians can adopt a more liberal attitude toward accepting DCD kidneys without significantly jeopardizing patient outcomes. Many currently discarded organs would certainly provide a favorable risk-benefit ratio to waitlisted individuals in terms of mortality and quality of life.
Nevertheless, a fundamental lack of accurate and validated criteria to assess kidney quality remains problematic. Several studies have investigated the use of pretransplant donor biopsies to guide donor organ acceptance, but this procedure is used infrequently, and its utility continues to be debated (reviewed in Stallone and Grandaliano8). Much of the dispute surrounding histology can potentially be circumvented by incorporating less subjective, cutting-edge technologies that provide functional data, including real-time information on metabolic activity that can guide clinical decision-making processes and determine donor organ use.
Magnetic resonance spectroscopy (MRS) is a powerful tool that can be harnessed to longitudinally assess ATP metabolism and be used to stratify the viability in the organ of interest, as described by Longchamps et al9 in this issue of Transplantation. ATP is the molecular currency that pays for all energetics. It is requisite for G protein-coupled receptor signal transduction, RNA and DNA synthesis, amino acid activation in protein synthesis, purinergic signaling (via receptors P2X and P2Y), and neurotransmission. ATP can be produced by 3 cellular processes: glycolysis (anaerobic metabolism, glucose is metabolized to pyruvate generating 2 ATP per cycle), oxidative phosphorylation (aerobic metabolism in mitochondria in which pyruvate is shunted through the citric acid cycle, generating >30 ATP per cycle), and beta oxidation (fatty acids are converted into acetyl-CoA, which also funnels into the citric acid cycle: dozens of ATP are produced per cycle). The generation of ATP is a reflection of cellular integrity and intact metabolic capacity. The measurement of ATP levels has direct translational relevance to organ bioenergetics and viability.
MRS can analyze each element of interest (all protons including hydrogen, as well as carbon-13 and phosphorus-31, which have physiological significance): the distribution of electrons within each atom produces a characteristic signature (magnetic field), which is read as a resonant frequency. The use of 31P-MRS dates back to nearly 70 years10 with further improvements in technique that improved spatial and spectral definition. Longchamp et al9 use MRS to identify both hydrogen (1H) and phosphorus (31P) signals to profile DCD kidneys. They use a porcine model of controlled warm ischemia, followed by hypothermic perfusion on an MRI-compatible prototypic machine perfusion device. The authors measured 3 phosphoryl groups of ATP (α, β, and terminal γ), and significant decreases in β and γ occur with increasing warm ischemic time, correlating well with histologic damage. Phosphomonoesters were also measured and, interestingly, remained consistently higher than ATP and unaffected by ischemic damage. This potentially reflects a precursor pool of phosphate groups to regenerate ATP during reperfusion. The group also used gadolinium to semiquantitatively evaluate corticomedullary flow and demonstrate correlation with histology.
This study shows promise in terms of adapting standard imaging techniques to adequately assess donor organ perfusion and metabolism, providing further opportunities to explore biomarkers that potentially determine “transplantability” and postoperative graft function. Currently, clinicians judge suitability for transplantation in DCD donors using a benchmark based solely on warm ischemic time but lack additional validated criteria. Longchamp et al demonstrate the possibility that donor kidneys can be objectively assessed in other ways, potentially pushing the boundaries that determine which donor organs are acceptable. Future applications of these techniques could also provide risk stratification for delayed graft function and an impetus to incorporate machine perfusion as standard-of-care. We acknowledge that the capacity to perform both machine perfusion and state-of-the-art analytical techniques such as spectroscopy will be limited to large quaternary transplant centers, but the addition of kidneys to the donor pool will help relieve the burden of organ shortage throughout the recipient pool.
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. Accessed May 13, 2020
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