Early Blood Transfusion After Kidney Transplantation Does Not Lead to dnDSA Development: The BloodIm Study

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Abstract

Outcomes after kidney transplantation are largely driven by the development of de novo donor-specific antibodies (dnDSA), which may be triggered by blood transfusion. In this single-center study, we investigated the link between early blood transfusion and dnDSA development in a mainly anti-thymocyte globulin (ATG)-induced kidney-transplant cohort. We retrospectively included all recipients of a kidney transplant performed between 2004 and 2015, provided they had >3 months graft survival. DSA screening was evaluated with a Luminex assay (Immucor). Early blood transfusion (EBT) was defined as the transfusion of at least one red blood-cell unit over the first 3 months post-transplantation, with an exhaustive report of transfusion. Patients received either anti-thymocyte globulins (ATG) or basiliximab induction, plus tacrolimus and mycophenolic acid maintenance immunosuppression. A total of 1088 patients received a transplant between 2004 and 2015 in our center, of which 981 satisfied our inclusion criteria. EBT was required for 292 patients (29.7%). Most patients received ATG induction (86.1%); the others received basiliximab induction (13.4%). dnDSA-free graft survival (dnDSA-GS) at 1-year post-transplantation was similar between EBT+ (2.4%) and EBT- (3.0%) patients (chi-squared p=0.73). There was no significant association between EBT and dnDSA-GS (univariate Cox’s regression, HR=0.88, p=0.556). In multivariate Cox’s regression, adjusting for potential confounders (showing a univariate association with dnDSA development), early transfusion remained not associated with dnDSA-GS (HR 0.76, p=0.449). However, dnDSA-GS was associated with pretransplantation HLA sensitization (HR=2.25, p=0.004), hemoglobin >10 g/dL (HR=0.39, p=0.029) and the number of HLA mismatches (HR=1.26, p=0.05). Recipient’s age, tacrolimus and mycophenolic-acid exposures, and graft rank were not associated with dnDSA-GS. Early blood transfusion did not induce dnDSAs in our cohort of ATG-induced patients, but low hemoglobin level was associated with dnDSAs-GS. This suggests a protective effect of ATG induction therapy on preventing dnDSA development at an initial stage post-transplantation.

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Most cited references 14

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The natural history of chronic allograft nephropathy.

Brian Nankivell, Richard J Borrows, Caroline L S Fung … (2003)

With improved immunosuppression and early allograft survival, chronic allograft nephropathy has become the dominant cause of kidney-transplant failure. We evaluated the natural history of chronic allograft nephropathy in a prospective study of 120 recipients with type 1 diabetes, all but 1 of whom had received kidney-pancreas transplants. We obtained 961 kidney-transplant-biopsy specimens taken regularly from the time of transplantation to 10 years thereafter. Two distinctive phases of injury were evident as chronic allograft nephropathy evolved. An initial phase of early tubulointerstitial damage from ischemic injury (P<0.05), prior severe rejection (P<0.01), and subclinical rejection (P<0.01) predicted mild disease by one year, which was present in 94.2 percent of patients. Early subclinical rejection was common (affecting 45.7 percent of biopsy specimens at three months), and the risk was increased by the occurrence of a prior episode of severe rejection and reduced by tacrolimus and mycophenolate therapy (both P<0.05) and gradually abated after one year. Both subclinical rejection and chronic rejection were associated with increased tubulointerstitial damage (P<0.01). Beyond one year, a later phase of chronic allograft nephropathy was characterized by microvascular and glomerular injury. Chronic rejection (defined as persistent subclinical rejection for two years or longer) was uncommon (5.8 percent). Progressive high-grade arteriolar hyalinosis with luminal narrowing, increasing glomerulosclerosis, and additional tubulointerstitial damage was accompanied by the use of calcineurin inhibitors. Nephrotoxicity, implicated in late ongoing injury, was almost universal at 10 years, even in grafts with excellent early histologic findings. By 10 years, severe chronic allograft nephropathy was present in 58.4 percent of patients, with sclerosis in 37.3 percent of glomeruli. Tubulointerstitial and glomerular damage, once established, was irreversible, resulting in declining renal function and graft failure. Chronic allograft nephropathy represents cumulative and incremental damage to nephrons from time-dependent immunologic and nonimmunologic causes. Copyright 2003 Massachusetts Medical Society

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Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence.

Bernard P. Halloran, A Matas, J. Reeve … (2012)

We prospectively studied kidney transplants that progressed to failure after a biopsy for clinical indications, aiming to assign a cause to every failure. We followed 315 allograft recipients who underwent indication biopsies at 6 days to 32 years posttransplant. Sixty kidneys progressed to failure in the follow-up period (median 31.4 months). Failure was rare after T-cell-mediated rejection and acute kidney injury and common after antibody-mediated rejection or glomerulonephritis. We developed rules for using biopsy diagnoses, HLA antibody and clinical data to explain each failure. Excluding four with missing information, 56 failures were attributed to four causes: rejection 36 (64%), glomerulonephritis 10 (18%), polyoma virus nephropathy 4 (7%) and intercurrent events 6 (11%). Every rejection loss had evidence of antibody-mediated rejection by the time of failure. Among rejection losses, 17 of 36 (47%) had been independently identified as nonadherent by attending clinicians. Nonadherence was more frequent in patients who progressed to failure (32%) versus those who survived (3%). Pure T-cell-mediated rejection, acute kidney injury, drug toxicity and unexplained progressive fibrosis were not causes of loss. This prospective cohort indicates that many actual failures after indication biopsies manifest phenotypic features of antibody-mediated or mixed rejection and also underscores the major role of nonadherence. © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

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Calcineurin inhibitor nephrotoxicity.

Maarten Naesens, Dirk Kuypers, Minnie Sarwal (2009)

The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question--whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway--remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.

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Author and article information

Contributors

Thomas Jouve: URI : https://loop.frontiersin.org/people/1353918

Johan Noble: URI : https://loop.frontiersin.org/people/739044

Céline Dard: URI : https://loop.frontiersin.org/people/1680289

Paolo Malvezzi: URI : https://loop.frontiersin.org/people/1538640

Lionel Rostaing: URI : https://loop.frontiersin.org/people/686462

Journal

Journal ID (nlm-ta): Front Immunol

Journal ID (iso-abbrev): Front Immunol

Journal ID (publisher-id): Front. Immunol.

Title: Frontiers in Immunology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-3224

Publication date (Electronic): 31 March 2022

Publication date Collection: 2022

Volume: 13

Electronic Location Identifier: 852079

Affiliations

[1] ¹ Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, University Hospital Grenoble , Grenoble, France

[2] ² Faculty of Health, Univ. Grenoble Alpes , Grenoble, France

[3] ³ Human Leukocyte Antigen (HLA) Laboratory, Etablissement Français du Sang (EFS) , La Tronche, France

[4] ⁴ Urology and Kidney Transplantation Department, University Hospital Grenoble , Grenoble, France

Author notes

Edited by: Guido Moll, Charité Universitätsmedizin Berlin, Germany

Reviewed by: Annelies De Weerd, Erasmus Medical Center, Netherlands; Sistiana Aiello, Mario Negri Pharmacological Research Institute (IRCCS), Italy

*Correspondence: Thomas Jouve, tjouve@ 123456chu-grenoble.fr

This article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology

Article

DOI: 10.3389/fimmu.2022.852079

PMC ID: 9009267

PubMed ID: 35432350

SO-VID: 1902e6bb-4672-46f5-85d0-8a8373304d61

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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 10 January 2022

Date accepted : 07 March 2022

Page count

Figures: 2, Tables: 4, Equations: 0, References: 14, Pages: 8, Words: 5047

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Early Blood Transfusion After Kidney Transplantation Does Not Lead to dnDSA Development: The BloodIm Study

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Most cited references 14

The natural history of chronic allograft nephropathy.

Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence.

Calcineurin inhibitor nephrotoxicity.

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