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    Organ Procurement and Transplantation Network. National data. Department U.S. of Health and Human Services. Accessed January 18, 2022. https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/

    • PubMed
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    Booker S. Lower respiratory SARS-CoV-2 testing for lung donors. Nine month post-implementation monitoring report. OPTN Ad Hoc Disease Transmission Advisory Committee. March 28, 2022. https://optn.transplant.hrsa.gov/media/0f0isl5k/data_report_dtac_full_20210726_rptn.pdf

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    Husain SA, et al. Characteristics and performance of unilateral kidney transplants from deceased donors. Clin J Am Soc Nephrol 2018; 13:118127. doi: 10.2215/CJN.06550617

    • PubMed
    • Search Google Scholar
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  • 4.

    Husain SA, et al. Association between declined offers of deceased donor kidney allograft and outcomes in kidney transplant candidates. JAMA Netw Open 2019; 2:e1910312. doi: 10.1001/jamanetworkopen.2019.10312

    • PubMed
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    Mohan S, et al. The weekend effect alters the procurement and discard rates of deceased donor kidneys in the United States. Kidney Int 2016; 90:157163. doi: 10.1016/j.kint.2016.03.007

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Aubert O, et al. Disparities in acceptance of deceased donor kidneys between the United States and France and estimated effects of increased US acceptance. JAMA Intern Med 2019; 179:13651374. doi: 10.1001/jamainternmed.2019.2322

    • PubMed
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    Liu C, et al. Association of deceased donor acute kidney injury with recipient graft survival. JAMA Netw Open 2020; 3:e1918634. doi: 10.1001/jamanetworkopen.2019.18634

    • PubMed
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  • 8.

    Reese PP, et al. Assessment of the utility of kidney histology as a basis for discarding organs in the United States: A comparison of international transplant practices and outcomes. J Am Soc Nephrol 2021; 32:397409. doi: 10.1681/ASN.2020040464

    • PubMed
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    Reese PP, et al. Associations between deceased-donor urine injury biomarkers and kidney transplant outcomes. J Am Soc Nephrol 2016; 27:15341543. doi: 10.1681/ASN.2015040345

    • PubMed
    • Search Google Scholar
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    Koyawala N, et al. Urine injury biomarkers are not associated with kidney transplant failure. Transplantation 2020; 104:12721279. doi: 10.1097/TP.0000000000002948

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    Puthumana J, et al. YKL-40 associates with renal recovery in deceased donor kidney transplantation. J Am Soc Nephrol 2017; 28:661670. doi: 10.1681/ASN.2016010091

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    Mansour SG, et al. Uromodulin to osteopontin ratio in deceased donor urine is associated with kidney graft outcomes. Transplantation 2021; 105:876885. doi: 10.1097/TP.0000000000003299

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Clinical Utility of Repair Markers in Deceased Donor Kidney Transplantation

Yumeng Wen Yumeng Wen, MD, and Chirag R. Parikh, MD, PhD, are with the Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD.

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Chirag R. Parikh Yumeng Wen, MD, and Chirag R. Parikh, MD, PhD, are with the Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD.

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In the United States, approximately 40,000 new patients are added to the waitlist for kidney transplantation each year, yet in 2021, only 19,000 on the waitlist received deceased donor kidney transplants (1). Because of the burdens of dialysis and the kidney shortage, nearly 8000 waitlisted patients died or became too sick to receive a transplant in 2021 (1). From 2010 through 2020, 18%–21% of procured kidneys were not transplanted, and kidney discards are on the rise (2). In 2021 alone, a total of 5080 kidneys were procured and then discarded. A minority of donor kidneys (<5%) are not transplanted due to medically justifiable reasons, but evidence, such as unilateral discards, weekend discards, and the high rate of organ turndown, all support the contention that the majority of discarded kidneys are potentially transplantable (35). This phenomenon is more pronounced in the United States than in other countries, with recent data suggesting that nearly two-thirds of discarded kidneys in the United States would have been transplanted in France (6).

Although a subset of these kidneys may be unsuitable for transplant, many kidneys—especially those from donors with acute kidney injury (AKI) or a high kidney donor risk index (KDRI)—may be unnecessarily discarded. Such kidneys are often biopsied to assess organ quality and undergo machine perfusion for organ preservation; however, >30% of these kidneys are still being discarded, despite growing evidence demonstrating comparable recipient graft outcomes as transplantation with kidneys from non-AKI donors (7). This high rate of organ discard likely results from the inability to accurately assess organ quality and predict recipient graft function by the KDRI and histological examination (8). Thus, better prognostic tools, especially non-invasive biomarker assessment that can be easily implemented, are needed to reduce organ discard and improve the availability of transplantation for patients with end stage kidney disease.

Biomarkers of tubular injury may have limited value in providing insights into the quality of deceased donor kidneys. Urinary neutrophil gelatinase-associated lipocalin (NGAL) was found to be associated with a lower glomerular filtration rate (GFR) at 6 months, only in those without delayed graft function (DGF), and the difference between the highest and lowest tertiles was only 3.15 mL/min/1.73 m2 (9). At 3 years after transplant, neither urinary NGAL nor kidney injury molecule 1 was associated with adverse graft outcomes (10). This is possible because ischemia-reperfusion injury is ubiquitous in the process of deceased donor kidney transplant; thus, donor kidney injury occurring before organ procurement may have a small contribution in determining recipients’ long-term graft function.

On the other hand, the lack of association between severe donor kidney injury and adverse recipient outcomes indicates significant recovery potential in these kidneys. Indeed, our previous work showed that deceased donor urinary chitinase 3-like protein 1 (YKL-40), a protein involved in the adaptive repair process after kidney injury, was strongly associated with a lower risk of DGF (11). More importantly, in recipients who developed DGF, those who received donor kidneys with the highest tertile of urinary YKL-40 had a 50% lower risk of graft failure compared with those receiving kidneys from donors with low urinary YKL-40 (Table 1) (11). In the same cohort of patients, urinary osteopontin (OPN), a protein with renoprotective effects via reducing tubular cell apoptosis and promoting repair of the injured tubule, was inversely associated with graft failure (12). Additionally, donor uromodulin (UMOD) may induce the expression of major histocompatibility complex II in bone marrow-derived mouse macrophages, and its urine level is associated with a higher risk of graft failure and lower recipients’ estimated GFR at 6 months. A lower donor urine UMOD/OPN ratio (e.g., <3 in our study), which may reflect a greater potential for adaptive repair and a lower risk of chronic rejection, is associated with a 27% risk reduction in graft failure than kidneys from a donor with a UMOD/OPN ratio >3. This evidence suggests that non-invasive biomarkers reflecting the kidney repair potential may provide more granular information for the organ quality beyond traditional donor characteristics and are valuable tools in facilitating decisions on organ procurement and allocation.

Table 1

Deceased donor urinary repair biomarkers are associated with lower risk of graft failure

Table 1

A gap between the knowledge derived from the above prospective cohort studies and clinical implementation is the availability of biomarker measurement results at the bedside to guide clinical decision-making. These biomarkers were measured using the gold standard immunoassay, which requires extensive laboratory expertise and may be infeasible to provide immediate results to the clinicians on-site. A potential solution is to develop lateral flow point-of-care devices for rapid testing for these biomarkers, similar to point-of-care antibody testing devices for assessing SARS-CoV-2 immunity. By providing rapid and more accurate assessments of the organ quality at the bedside, these non-invasive biomarkers can potentially change the landscape of allocation, reduce the number of discarded deceased donor kidneys, and improve organ availability to countless patients on the waiting list.

References

  • 1.

    Organ Procurement and Transplantation Network. National data. Department U.S. of Health and Human Services. Accessed January 18, 2022. https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/

    • PubMed
    • Export Citation
  • 2.

    Booker S. Lower respiratory SARS-CoV-2 testing for lung donors. Nine month post-implementation monitoring report. OPTN Ad Hoc Disease Transmission Advisory Committee. March 28, 2022. https://optn.transplant.hrsa.gov/media/0f0isl5k/data_report_dtac_full_20210726_rptn.pdf

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Husain SA, et al. Characteristics and performance of unilateral kidney transplants from deceased donors. Clin J Am Soc Nephrol 2018; 13:118127. doi: 10.2215/CJN.06550617

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Husain SA, et al. Association between declined offers of deceased donor kidney allograft and outcomes in kidney transplant candidates. JAMA Netw Open 2019; 2:e1910312. doi: 10.1001/jamanetworkopen.2019.10312

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Mohan S, et al. The weekend effect alters the procurement and discard rates of deceased donor kidneys in the United States. Kidney Int 2016; 90:157163. doi: 10.1016/j.kint.2016.03.007

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Aubert O, et al. Disparities in acceptance of deceased donor kidneys between the United States and France and estimated effects of increased US acceptance. JAMA Intern Med 2019; 179:13651374. doi: 10.1001/jamainternmed.2019.2322

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Liu C, et al. Association of deceased donor acute kidney injury with recipient graft survival. JAMA Netw Open 2020; 3:e1918634. doi: 10.1001/jamanetworkopen.2019.18634

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Reese PP, et al. Assessment of the utility of kidney histology as a basis for discarding organs in the United States: A comparison of international transplant practices and outcomes. J Am Soc Nephrol 2021; 32:397409. doi: 10.1681/ASN.2020040464

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Reese PP, et al. Associations between deceased-donor urine injury biomarkers and kidney transplant outcomes. J Am Soc Nephrol 2016; 27:15341543. doi: 10.1681/ASN.2015040345

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Koyawala N, et al. Urine injury biomarkers are not associated with kidney transplant failure. Transplantation 2020; 104:12721279. doi: 10.1097/TP.0000000000002948

  • 11.

    Puthumana J, et al. YKL-40 associates with renal recovery in deceased donor kidney transplantation. J Am Soc Nephrol 2017; 28:661670. doi: 10.1681/ASN.2016010091

  • 12.

    Mansour SG, et al. Uromodulin to osteopontin ratio in deceased donor urine is associated with kidney graft outcomes. Transplantation 2021; 105:876885. doi: 10.1097/TP.0000000000003299

    • PubMed
    • Search Google Scholar
    • Export Citation
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