Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Feedback
    • Reprint Information
    • Subscriptions
  • ASN Kidney News
  • Other
    • ASN Publications
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • ASN Publications
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Feedback
    • Reprint Information
    • Subscriptions
  • ASN Kidney News
  • Visit ASN on Facebook
  • Follow CJASN on Twitter
  • CJASN RSS
  • Community Forum
Editorials
You have accessRestricted Access

Medical Therapies to Reduce Delayed Graft Function and Improve Long-Term Graft Survival

Are We Making Progress?

Mary Ann Lim and Roy D. Bloom
CJASN January 2020, 15 (1) 13-15; DOI: https://doi.org/10.2215/CJN.13961119
Mary Ann Lim
Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Roy D. Bloom
Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading
  • delayed graft function
  • Graft Survival
  • Transplants
  • Graft Rejection

Delayed graft function (DGF) is defined by the United Network for Organ Sharing (UNOS) as the need for at least one dialysis treatment in the first week after kidney transplantation. Because dialysis may be performed for indications unrelated to graft dysfunction (e.g., hyperkalemia or fluid overload), the UNOS definition of DGF is widely acknowledged to be imperfect. However, it is used for uniformity in data reporting, and in most DGF studies. With rates reported to range between 25% and 30%, DGF has been associated in outcomes studies with increased hospital stay, increased rejection, and shorter graft survival (1). The mechanism underlying DGF, in its truest sense, is thought to primarily be related to ischemia-reperfusion injury, with ischemia from a variety of donor characteristics superimposed upon immune and inflammatory responses peri-transplant and postreperfusion, leading to acute tubular necrosis.

Given its important clinical implications, DGF has long been an active area of basic and clinical investigation. In this issue of CJASN, Huang et al. report the use of a novel therapeutic intervention for DGF (2), adding to the many treatments that have been tested in clinical trials and either published previously or currently remain under investigation. As shown in Table 1, most published studies have been disappointing in that they have shown minimal or no difference in DGF rates with intervention, or no eventual effect on allograft function or survival (3–7). For example, an initial study on donor therapy with dopamine showed promise, with reduced recipient dialysis needs; however, a larger-scale study ultimately failed to show improvement in 5-year graft survival (4). Similarly, hypothermic machine perfusion of deceased donor kidneys, as compared with cold storage, has been shown to decrease rates of DGF; however, the effect on long-term allograft survival is unknown (7). Thus far, the only intervention shown, albeit in a small, open-label, single-center study, to reduce DGF that has gained traction in clinical practice is the use of intraoperative rabbit anti-thymocyte globulin administered before reperfusion; however, no larger-scale, blinded trials have been undertaken to validate this (8). Delayed use or minimization of calcineurin inhibitors has been assumed to lower DGF rates or shorten DGF duration, but evidence supporting this strategy and/or how this translates into longer-term outcomes is lacking.

View this table:
  • View inline
  • View popup
Table 1.

Selected published and registered randomized, controlled DGF trials

The study reported herein by Huang et al. represents post hoc follow-up of the original randomized trial of 70 deceased donor kidney recipients at risk for DGF, randomized 1:1 to receive C1 esterase inhibitor or placebo intraoperatively and again at 24 hours (9). Although the intervention did not lead to decreased rates of DGF, there was a trend toward shorter duration of this complication. The authors have now examined outcomes after 3.5 years in the form of graft failure and death, as well as eGFR slopes using linear mixed-effects model with random slopes and intercepts. While overall graft failure was not significantly different between the two groups, death-censored graft loss occurred in seven participants in the placebo group compared with one patient in the treatment group (P=0.03), whereas there were no deaths in the placebo group versus three in the treatment group (P=0.09). Functionally, the GFR slope rate declined in the placebo group (−4 ml/min per 1.73 m2 per year; 95% confidence interval, −8 to −0.1) but remained stable in the treatment group (0.5 ml/min per 1.73 m2 per year; 95% confidence interval, −4 to 5). Huang et al. conclude that treatment of patients at risk for ischemia-reperfusion injury with C1 esterase inhibitor was associated with a lower cumulative incidence of death-censored graft failure and a higher GFR at 3.5 years (P=0.05).

Although the findings of this well matched, randomized, double-blind, placebo-controlled trial are interesting, the sample size is small and the low percentage of black participants restricts the study generalizability, as pointed out by the investigators. Furthermore, the absence of other key information additionally constrains how one should interpret these findings. For example, not providing cause of graft failure limits the ability to determine whether the observed effect of C1 esterase inhibitor on death-censored graft survival was in any way related to an effect on DGF or ischemia-reperfusion injury. It is also unclear how graft loss and death was accounted for in the GFR slope analysis and how this might have affected their findings. Finally, although the authors state that the placebo group’s graft failure rate is similar to published rates for recipients of kidneys with a kidney donor profile index (KDPI)>85%, it is important to note that only 30% of placebo group patients received such kidneys, in which case the expected graft failure rate should be lower (2).

The rationale for evaluating C1 esterase inhibition to prevent DGF makes sense, given that (1) the predominant underlying mechanism is thought to be from ischemia-reperfusion injury, (2) the classic and mannose-binding lectin pathway have been implicated in ischemia-reperfusion injury, and (3) animal data have shown that targeting these two pathways prevents and/or attenuates ischemia-reperfusion injury and immune activation (2). Because prior research has not yielded much in the way of interventions to reduce DGF and improve allograft outcomes, Huang et al.’s preliminary investigation into C1 esterase is both commendable and worth considering to expand into a larger, more robust, multicenter trial. That said, it is important to point out that although the three treatment group deaths observed in their study all occurred more than 1.5 years after C1 esterase inhibitor treatment and may be unrelated to its administration, this adverse outcome nevertheless constitutes a safety signal that warrants close monitoring if this therapy were to be investigated further. A final consideration is whether enthusiasm for C1 esterase inhibition in this setting should be tempered by the fact that recent multicenter, randomized, controlled trials evaluating eculizumab in DGF failed to demonstrate a benefit to blockade of complement activation (e.g., Schröppel et al. [3]). Although the answer to this question is unknowable at present, it is possible that blocking a more proximal site of action on the complement pathway and/or the inhibition of noncomplement pathways (i.e., inhibition of activated factor XII, active kallikrein, factor XIa, and thrombin) by the C1 esterase inhibitor could result in a different effect, as some have proposed (10).

In summary, DGF remains a major clinical challenge for the transplant practitioner. In addition to efforts aimed at better defining DGF in the context of ischemia-reperfusion injury, and research focused on more clearly elucidating its biology, a growing number of treatment strategies and interventions are being investigated, at the level of donors, organ preservation, and therapies administered perioperatively to recipients (Table 1). The complement pathway, a major component of the innate immune system, is being increasingly recognized as a potential mediator of ischemia-reperfusion injury. For this reason, the innovative approach undertaken by Huang et al. should be applauded, but more answers are clearly needed regarding the safety and efficacy of C1 esterase inhibition in preventing DGF. Finally, at a fundamental level, understanding how exactly DGF leads to increased rejection risk and worse long-term graft survival remains a critical unmet need in kidney transplantation. We look forward to the results of the several ongoing studies that are currently underway in this fertile area of investigation.

Disclosures

Dr. Bloom reports grants from Shire and Vitaeris, grants and personal fees from AbbVie, CareDx, and Veloxis, and personal fees from CSL Behring, Merck, National Kidney Foundation, Paladin Labs, and UpToDate, all outside the submitted work. Dr. Lim has nothing to disclose.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • See related article, “Three-Year Outcomes of a Randomized, Double-Blind, Placebo-Controlled Study Assessing Safety and Efficacy of C1 Esterase Inhibitor for Prevention of Delayed Graft Function in Deceased Donor Kidney Transplant Recipients,” on pages 109–116.

  • Copyright © 2020 by the American Society of Nephrology

References

  1. ↵
    1. Mannon RB
    : Delayed graft function: The AKI of kidney transplantation. Nephron 140: 94–98, 2018pmid:30007955
    OpenUrlPubMed
  2. ↵
    1. Huang E,
    2. Vo A,
    3. Choi J,
    4. Ammerman N,
    5. Lim K,
    6. Sethi S,
    7. Kim I,
    8. Kumar S,
    9. Najjar R,
    10. Peng A,
    11. Jordan SC
    : Three-year outcomes of a randomized, double-blind, placebo-controlled study assessing safety and efficacy of C1 esterase inhibitor for prevention of delayed graft function in deceased donor kidney transplant recipients. Clin J Am Soc Nephrol 15: 109–116, 2020
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Schröppel B,
    2. Akalin E,
    3. Baweja M,
    4. Bloom RD,
    5. Florman S,
    6. Goldstein M,
    7. Haydel B,
    8. Hricik DE,
    9. Kulkarni S,
    10. Levine M,
    11. Mehrotra A,
    12. Patel A,
    13. Poggio ED,
    14. Ratner L,
    15. Shapiro R,
    16. Heeger PS
    : Peritransplant eculizumab does not prevent delayed graft function in deceased donor kidney transplant recipients: Results of two randomized controlled pilot trials [published online ahead of print August 26, 2019]. Am J Transplant doi: 10.1111/ajt.15580pmid:31452319
    OpenUrlPubMed
  4. ↵
    1. Schnuelle P,
    2. Schmitt WH,
    3. Weiss C,
    4. Habicht A,
    5. Renders L,
    6. Zeier M,
    7. Drüschler F,
    8. Heller K,
    9. Pisarski P,
    10. Banas B,
    11. Krämer BK,
    12. Jung M,
    13. Lopau K,
    14. Olbricht CJ,
    15. Weihprecht H,
    16. Schenker P,
    17. De Fijter JW,
    18. Yard BA,
    19. Benck U
    : Effects of dopamine donor Pretreatment on graft survival after kidney transplantation: A randomized trial. Clin J Am Soc Nephrol 12: 493–501, 2017pmid:28213388
    OpenUrlAbstract/FREE Full Text
    1. Sureshkumar KK,
    2. Hussain SM,
    3. Ko TY,
    4. Thai NL,
    5. Marcus RJ
    : Effect of high-dose erythropoietin on graft function after kidney transplantation: A randomized, double-blind clinical trial. Clin J Am Soc Nephrol 7: 1498–1506, 2012pmid:22745272
    OpenUrlAbstract/FREE Full Text
    1. Gaber AO,
    2. Mulgaonkar S,
    3. Kahan BD,
    4. Woodle ES,
    5. Alloway R,
    6. Bajjoka I,
    7. Jensik S,
    8. Klintmalm GB,
    9. Patton PR,
    10. Wiseman A,
    11. Lipshutz G,
    12. Kupiec-Weglinski J,
    13. Gaber LW,
    14. Katz E,
    15. Irish W,
    16. Squiers EC,
    17. Hemmerich S
    : YSPSL (rPSGL-Ig) for improvement of early renal allograft function: A double-blind, placebo-controlled, multi-center Phase IIa study. Clin Transplant 25: 523–533, 2011pmid:20573162
    OpenUrlPubMed
  5. ↵
    1. Tedesco-Silva H,
    2. Mello Offerni JC,
    3. Ayres Carneiro V,
    4. Ivani de Paula M,
    5. Neto ED,
    6. Brambate Carvalhinho Lemos F,
    7. Requião Moura LR,
    8. Pacheco E Silva Filho A,
    9. de Morais Cunha MF,
    10. Francisco da Silva E,
    11. Miorin LA,
    12. Demetrio DP,
    13. Luconi PS,
    14. da Silva Luconi WT,
    15. Bobbio SA,
    16. Kuschnaroff LM,
    17. Noronha IL,
    18. Braga SL,
    19. Barsante RC,
    20. Mendes Moreira JC,
    21. Fernandes-Charpiot IMM,
    22. Abbud-Filho M,
    23. Modelli de Andrade LG,
    24. Dalsoglio Garcia P,
    25. Tanajura Santamaria Saber L,
    26. Fernandes Laurindo A,
    27. Chocair PR,
    28. Cuvello Neto AL,
    29. Zanocco JA,
    30. Duboc de Almeida Soares Filho AJ,
    31. Ferreira Aguiar W,
    32. Medina Pestana J
    : Randomized trial of machine perfusion versus cold storage in recipients of deceased donor kidney transplants with high incidence of delayed graft function. Transplant Direct 3: e155, 2017pmid:28573190
    OpenUrlPubMed
  6. ↵
    1. Goggins WC,
    2. Pascual MA,
    3. Powelson JA,
    4. Magee C,
    5. Tolkoff-Rubin N,
    6. Farrell ML,
    7. Ko DS,
    8. Williams WW,
    9. Chandraker A,
    10. Delmonico FL,
    11. Auchincloss H,
    12. Cosimi AB
    : A prospective, randomized, clinical trial of intraoperative versus postoperative Thymoglobulin in adult cadaveric renal transplant recipients. Transplantation 76: 798–802, 2003pmid:14501856
    OpenUrlCrossRefPubMed
  7. ↵
    1. Jordan SC,
    2. Choi J,
    3. Aubert O,
    4. Haas M,
    5. Loupy A,
    6. Huang E,
    7. Peng A,
    8. Kim I,
    9. Louie S,
    10. Ammerman N,
    11. Najjar R,
    12. Puliyanda D,
    13. Vo A
    : A phase I/II, double-blind, placebo-controlled study assessing safety and efficacy of C1 esterase inhibitor for prevention of delayed graft function in deceased donor kidney transplant recipients. Am J Transplant 18: 2955–2964, 2018pmid:29637714
    OpenUrlPubMed
  8. ↵
    1. Berger M,
    2. Lefaucheur C,
    3. Jordan SC
    : Update on C1 esterase inhibitor in human solid organ transplantation. Transplantation 103: 1763–1775, 2019pmid:30946220
    OpenUrlPubMed
PreviousNext
Back to top

In this issue

Clinical Journal of the American Society of Nephrology: 15 (1)
Clinical Journal of the American Society of Nephrology
Vol. 15, Issue 1
January 07, 2020
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in CJASN.
Enter multiple addresses on separate lines or separate them with commas.
Medical Therapies to Reduce Delayed Graft Function and Improve Long-Term Graft Survival
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Medical Therapies to Reduce Delayed Graft Function and Improve Long-Term Graft Survival
Mary Ann Lim, Roy D. Bloom
CJASN Jan 2020, 15 (1) 13-15; DOI: 10.2215/CJN.13961119

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Medical Therapies to Reduce Delayed Graft Function and Improve Long-Term Graft Survival
Mary Ann Lim, Roy D. Bloom
CJASN Jan 2020, 15 (1) 13-15; DOI: 10.2215/CJN.13961119
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Disclosures
    • Footnotes
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

  • APOL1 Kidney Risk Variants and Acute Kidney Injury in Those with COVID-19
  • Telehealth and Kidney Disease Care
  • Time to Abandon Kidney Biopsy to Diagnose Membranous Nephropathy?
Show more Editorials

Cited By...

  • A functional TGFB1 polymorphism in the donor associates with long-term graft survival after kidney transplantation
  • Google Scholar

Similar Articles

Related Articles

  • Three-Year Outcomes of a Randomized, Double-Blind, Placebo-Controlled Study Assessing Safety and Efficacy of C1 Esterase Inhibitor for Prevention of Delayed Graft Function in Deceased Donor Kidney Transplant Recipients
  • PubMed
  • Google Scholar

Keywords

  • delayed graft function
  • graft survival
  • transplants
  • graft rejection

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Trainee of the Year
  • Author Resources
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • CJASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About CJASN
  • CJASN Email Alerts
  • CJASN Key Impact Information
  • CJASN Podcasts
  • CJASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe to ASN Journals

© 2022 American Society of Nephrology

Print ISSN - 1555-9041 Online ISSN - 1555-905X

Powered by HighWire