Skip to main content

Advertisement

SpringerLink
Log in

Accelerated rejection, thrombosis, and graft failure with angiotensin II type 1 receptor antibodies

  • Brief Report
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background

Angiotensin II type 1 receptor antibodies (AT1R-Abs) have been implicated in renal transplant rejection and failure; however, the mechanism of allograft damage, patterns of clinical presentation, and response to desensitization of AT1R-Abs have not been clearly established.

Case diagnosis/treatment

We present the case of a 7-year-old boy with preformed AT1R-Abs who developed accelerated vascular and cellular rejection and renal allograft thrombosis despite desensitization and treatment with angiotensin receptor blockade. Although an association between AT1R-Abs and microvascular occlusion has been previously described, we are the first to describe an association between AT1R-Abs and renal artery thrombosis, leading to devastating early allograft failure.

Conclusions

This case highlights the risk of allograft thrombosis associated with AT1R-Abs and illustrates that previous treatments utilized for AT1R-Abs may not always be effective. Further studies are needed to better characterize the mechanisms of AT1R-Ab pathogenesis and to establish safe levels of AT1R-Abs both pre- and post-transplantation. Given the outcome of this patient and the evidence of pro-coagulatory effects of AT1R-Abs, we suggest that the presence of AT1R-Ab may be a risk factor for thrombosis. The role of treatment with anti-coagulation and novel immunomodulatory agents such as tocilizumab and bortezomib require further investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  1. Morris PJ, Williams GM, Hume DM, Mickey MR, Terasaki PI (1968) Serotyping for homotransplantation. XII. Occurrence of cytotoxic antibodies following kidney transplantation in man. Transplantation 6:392–399

    Article  CAS  PubMed  Google Scholar 

  2. Tait BD, Susal C, Gebel HM, Nickerson PW, Zachary AA, Claas FH, Reed EF, Bray RA, Campbell P, Chapman JR, Coates PT, Colvin RB, Cozzi E, Doxiadis II, Fuggle SV, Gill J, Glotz D, Lachmann N, Mohanakumar T, Suciu-Foca N, Sumitran-Holgersson S, Tanabe K, Taylor CJ, Tyan DB, Webster A, Zeevi A, Opelz G (2013) Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation 95:19–47

    Article  CAS  PubMed  Google Scholar 

  3. Mohan S, Palanisamy A, Tsapepas D, Tanriover B, Crew RJ, Dube G, Ratner LE, Cohen DJ, Radhakrishnan J (2012) Donor-specific antibodies adversely affect kidney allograft outcomes. J Am Soc Nephrol 23:2061–2071

    Article  PubMed Central  PubMed  Google Scholar 

  4. Dragun D, Muller DN, Brasen JH, Fritsche L, Nieminen-Kelha M, Dechend R, Kintscher U, Rudolph B, Hoebeke J, Eckert D, Mazak I, Plehm R, Schonemann C, Unger T, Budde K, Neumayer HH, Luft FC, Wallukat G (2005) Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection. N Engl J Med 352:558–569

    Article  CAS  PubMed  Google Scholar 

  5. Reinsmoen NL, Lai CH, Heidecke H, Haas M, Cao K, Ong G, Naim M, Wang Q, Mirocha J, Kahwaji J, Vo AA, Jordan SC, Dragun D (2010) Anti-angiotensin type 1 receptor antibodies associated with antibody-mediated rejection in donor HLA antibody negative patients. Transplantation 90:1473–1477

    Article  CAS  PubMed  Google Scholar 

  6. Giral M, Foucher Y, Dufay A, Van Huyen JP, Renaudin K, Moreau A, Philippe A, Hegner B, Dechend R, Heidecke H, Brouard S, Cesbron A, Castagnet S, Devys A, Soulillou JP, Dragun D (2013) Pretransplant sensitization against angiotensin II type 1 receptor is a risk factor for acute rejection and graft loss. Am J Transplant 13:2567–2576

    Article  CAS  PubMed  Google Scholar 

  7. Taniguchi M, Rebellato LM, Cai J, Hopfield J, Briley KP, Haisch CE, Catrou PG, Bolin P, Parker K, Kendrick WT, Kendrick SA, Harland RC, Terasaki PI (2013) Higher risk of kidney graft failure in the presence of anti-angiotensin II type-1 receptor antibodies. Am J Transplant 13:2577–2589

    Article  CAS  PubMed  Google Scholar 

  8. Zhang Q, Cecka JM, Gjertson DW, Ge P, Rose ML, Patel JK, Ardehali A, Kobashigawa JA, Fishbein MC, Reed EF (2011) HLA and MICA: targets of antibody-mediated rejection in heart transplantation. Transplantation 91:1153–1158

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Kamińska M, Mogielnicki A, Stankiewicz A, Kramkowski K, Domaniewski T, Buczko W, Chabielska E (2005) Angiotensin II via AT1 receptor accelerates arterial thrombosis in renovascular hypertensive rats. J Physiol Pharmacol 56:571–585

    PubMed  Google Scholar 

  10. Dobado-Berrios PM, Lopez-Pedrera C, Velasco F, Cuadrado MJ (2001) The role of tissue factor in the antiphospholipid syndrome. Arthritis Rheum 44:2467–2476

    Article  CAS  PubMed  Google Scholar 

  11. Holschermann H, Bohle RM, Schmidt H, Zeller H, Fink L, Stahl U, Grimm H, Tillmanns H, Haberbosch W (2000) Hirudin reduces tissue factor expression and attenuates graft arteriosclerosis in rat cardiac allografts. Circulation 102:357–363

    Article  CAS  PubMed  Google Scholar 

  12. Lukitsch I, Kehr J, Chaykovska L, Wallukat G, Nieminen-Kelha M, Batuman V, Dragun D, Gollasch M (2012) Renal ischemia and transplantation predispose to vascular constriction mediated by angiotensin II type 1 receptor-activating antibodies. Transplantation 94:8–13

    Article  CAS  PubMed  Google Scholar 

  13. Samama MM (2011) The mechanism of action of rivaroxaban–an oral, direct Factor Xa inhibitor–compared with other anticoagulants. Thromb Res 127:497–504

    Article  CAS  PubMed  Google Scholar 

  14. Berry CN, Girardot C, Lecoffre C, Lunven C (1994) Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and recombinant Hirudin. Thromb Haemost 72:381–386

    CAS  PubMed  Google Scholar 

  15. Giugliano RP, Wiviott SD, Stone PH, Simon DI, Schweiger MJ, Bouchard A, Leesar MA, Goulder MA, Deitcher SR, McCabe CH, Braunwald E, Investigators A-T- (2007) Recombinant nematode anticoagulant protein c2 in patients with non-ST-segment elevation acute coronary syndrome: the ANTHEM-TIMI-32 trial. J Am Coll Cardiol 49:2398–2407

    Article  CAS  PubMed  Google Scholar 

  16. Lee A, Agnelli G, Buller H, Ginsberg J, Heit J, Rote W, Vlasuk G, Costantini L, Julian J, Comp P, van Der Meer J, Piovella F, Raskob G, Gent M (2001) Dose–response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement. Circulation 104:74–78

    Article  CAS  PubMed  Google Scholar 

  17. Amaral LM, Kiprono L, Cornelius DC, Shoemaker C, Wallace K, Moseley J, Wallukat G, Martin JN Jr, Dechend R, LaMarca B (2014) Progesterone supplementation attenuates hypertension and the autoantibody to the angiotensin II type I receptor in response to elevated interleukin-6 during pregnancy. Am J Obstet Gynecol 211(158):e151–e156

    Google Scholar 

  18. Kim I, Wu G, Chai NN, Klein AS, Jordan S (2014) Anti-interleukin 6 receptor antibodies attenuate antibody recall responses in a mouse model of allosensitization. Transplantation. doi:10.1097/TP.0000000000000437

    Google Scholar 

  19. Perry DK, Burns JM, Pollinger HS, Amiot BP, Gloor JM, Gores GJ, Stegall MD (2009) Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production. Am J Transplant 9:201–209

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank the Casey Lee Ball Foundation and the UCLA Children’s Discovery and Innovation (CDI) and Today and Tomorrow’s Children Fund (TTCF) for supporting this work.

Conflict of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Division of Nephrology, University of California Los Angeles, David Geffen School of Medicine at UCLA, PO Box 951752, Los Angeles, CA, 90095, USA

    Meghan H. Pearl, Robert B. Ettenger & Eileen W. Tsai

  2. Department of Pathology and Laboratory Medicine, University of California Los Angeles Immunogenetics Center, 15-20 Rehab, 1000 Veteran Ave, Los Angeles, CA, 90095-1652, USA

    Richard K. Leuchter, Elaine F. Reed & Qiuheng Zhang

Authors
  1. Meghan H. Pearl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard K. Leuchter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elaine F. Reed
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiuheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert B. Ettenger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eileen W. Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meghan H. Pearl.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pearl, M.H., Leuchter, R.K., Reed, E.F. et al. Accelerated rejection, thrombosis, and graft failure with angiotensin II type 1 receptor antibodies. Pediatr Nephrol 30, 1371–1374 (2015). https://doi.org/10.1007/s00467-015-3123-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-015-3123-5

Keywords

Search

Navigation