Skip to main content
SpringerLink
Log in

Ferumoxytol Is Not Retained in Kidney Allografts in Patients Undergoing Acute Rejection

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

To evaluate whether ultrasmall superparamagnetic iron oxide nanoparticle (USPIO)-enhanced magnetic resonance imaging (MRI) can detect allograft rejection in pediatric kidney transplant patients.

Procedures

The USPIO ferumoxytol has a long blood half-life and is phagocytosed by macrophages. In an IRB-approved single-center prospective clinical trial, 26 pediatric patients and adolescents (age 10–26 years) with acute allograft rejection (n = 5), non-rejecting allografts (n = 13), and normal native kidneys (n = 8) underwent multi-echo T2* fast spoiled gradient-echo (FSPGR) MRI after intravenous injection (p.i.) of 5 mg Fe/kg ferumoxytol. T2* relaxation times at 4 h p.i. (perfusion phase) and more than 20 h p.i. (macrophage phase) were compared with biopsy results. The presence of rejection was assessed using the Banff criteria, and the prevalence of macrophages on CD163 immunostains was determined based on a semi-quantitative scoring system. MRI and histology data were compared among patient groups using t tests, analysis of variance, and regression analyses with a significance threshold of p < 0.05.

Results

At 4 h p.i., mean T2* values were 6.6 ± 1.5 ms for native kidneys and 3.9 ms for one allograft undergoing acute immune rejection. Surprisingly, at 20–24 h p.i., one rejecting allograft showed significantly prolonged T2* relaxation times (37.0 ms) compared to native kidneys (6.3 ± 1.7 ms) and non-rejecting allografts (7.6 ± 0.1 ms). Likewise, three additional rejecting allografts showed significantly prolonged T2* relaxation times compared to non-rejecting allografts at later post-contrast time points, 25–97 h p.i. (p = 0.008). Histological analysis revealed edema and compressed microvessels in biopsies of rejecting allografts. Allografts with and without rejection showed insignificant differences in macrophage content on histopathology (p = 0.44).

Conclusion

After ferumoxytol administration, renal allografts undergoing acute rejection show prolonged T2* values compared to non-rejecting allografts. Since histology revealed no significant differences in macrophage content, the increasing T2* value is likely due to the combined effect of reduced perfusion and increased edema in rejecting allografts.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Thiruchelvam PT, Willicombe M, Hakim N et al (2011) Renal transplantation. Br Med J 343:d7300

    Article  Google Scholar 

  2. Magee JC, Bucuvalas JC, Farmer DG et al (2004) Pediatric transplantation. Am J Transplant 4(Suppl 9):54–71

    Article  PubMed  Google Scholar 

  3. McEnery PT, Stablein DM, Arbus G, Tejani A (1992) Renal transplantation in children. A report of the north American pediatric renal transplant cooperative study. N Engl J Med 326:1727–1732

    Article  CAS  PubMed  Google Scholar 

  4. Ogura Y, Krams SM, Martinez OM et al (2000) Radiolabeled Annexin V imaging: diagnosis of allograft rejection in an experimental rodent model of liver transplantation 1. Radiology 214:795–800

    Article  CAS  PubMed  Google Scholar 

  5. Martins F, Souza S, Gonçalves R et al (2004) Preliminary results of [99mTc] OKT3 scintigraphy to evaluate acute rejection in renal transplants. Transplant Proc 36:2664–2667

    Article  CAS  PubMed  Google Scholar 

  6. De Souza SL, Da Fonseca LB, Gonçalves RT et al (2004) Diagnosis of renal allograft rejection and acute tubular necrosis by 99mTc-mononuclear leukocyte imaging. Transplant Proc 36:2997–3001

    Article  Google Scholar 

  7. Cosgrove DO, Chan KE (2008) Renal transplants: what ultrasound can and cannot do. Ultrasound Q 24:77–87

    Article  PubMed  Google Scholar 

  8. Bashir MR, Jaffe TA, Brennan TV et al (2013) Renal transplant imaging using magnetic resonance angiography with a nonnephrotoxic contrast agent. Transplantation 96:91–96

    Article  CAS  PubMed  Google Scholar 

  9. Wentland AL, Sadowski EA, Djamali A et al (2009) Quantitative MR measures of intrarenal perfusion in the assessment of transplanted kidneys: initial experience. Acad Radiol 16:1077–1085

    Article  PubMed  PubMed Central  Google Scholar 

  10. Laissy J-P, Idée J-M, Fernandez P et al (2006) Magnetic resonance imaging in acute and chronic kidney diseases: present status. Nephron Clin Pract 103:c50–c57

    Article  PubMed  Google Scholar 

  11. Szolar DH, Preidler K, Ebner F et al (1997) Functional magnetic resonance imaging of human renal allografts during the post-transplant period: preliminary observations. Magnet Reson Imaging 15(7):727–735

    Article  CAS  Google Scholar 

  12. Kalb B, Martin DR, Salman K et al (2008) Kidney transplantation: structural and functional evaluation using MR Nephro-urography. J Magnet Reson Imaging 28:805–822

    Article  Google Scholar 

  13. Wu YL, Ye Q, Eytan DF et al (2013) Magnetic resonance imaging investigation of macrophages in acute cardiac allograft rejection after heart transplantation. Circ Cardiovasc Imaging 6:965–973

    Article  PubMed  Google Scholar 

  14. Kriz J, Jirák D, Girman P et al (2005) Magnetic resonance imaging of pancreatic islets in tolerance and rejection. Transplantation 80:1596–1603

    Article  PubMed  Google Scholar 

  15. Chae EY, Song EJ, Sohn JY et al (2010) Allogeneic renal graft rejection in a rat model: in vivo MR imaging of the homing trait of macrophages 1. Radiology 256:847–854

    Article  PubMed  Google Scholar 

  16. Hauger O, Grenier N, Deminère C et al (2007) USPIO-enhanced MR imaging of macrophage infiltration in native and transplanted kidneys: initial results in humans. Europ Radiol 17:2898–2907

    Article  Google Scholar 

  17. Ricardo SD, van Goor H, Eddy AA (2008) Macrophage diversity in renal injury and repair. J Clin Invest 118:3522–3530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Magil AB (2009) Monocytes/macrophages in renal allograft rejection. Transplant Rev 23:199–208

    Article  Google Scholar 

  19. Tinckam KJ, Djurdjev O, Magil AB (2005) Glomerular monocytes predict worse outcomes after acute renal allograft rejection independent of C4d status. Kidney Int 68:1866–1874

    Article  PubMed  Google Scholar 

  20. Corot C, Robert P, Idee JM, Port M (2006) Recent advances in iron oxide nanocrystal technology for medical imaging. Adv Drug Deliv Rev 58:1471–1504

    Article  CAS  PubMed  Google Scholar 

  21. Daldrup-Link HE, Golovko D, Ruffell B et al (2011) MRI of tumor-associated macrophages with clinically applicable iron oxide nanoparticles. Clin Cancer Res 17:5695–5704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Aghighi M, Golovko D, Ansari C et al (2015) Imaging tumor necrosis with Ferumoxytol. PLoS One 10:e0142665

    Article  PubMed  PubMed Central  Google Scholar 

  23. Muehe AM, Feng D, von Eyben R et al (2015) Safety report of Ferumoxytol for magnetic resonance imaging in children and young adults. Investig Radiol 51:221–227

    Article  Google Scholar 

  24. Levey AS, Stevens LA (2010) Estimating GFR using the CKD epidemiology collaboration (CKD-EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, and better risk predictions. Am J Kidnet Dis 55:622–627

    Article  Google Scholar 

  25. AMAG Pharmaceuticals, Inc. (2009) Feraheme (ferumoxytol) package insert. Lexington, MA

  26. Balakrishnan VS, Rao M, Kausz AT et al (2009) Physicochemical properties of ferumoxytol, a new intravenous iron preparation. Eur J Clin Investig 39:489–496

    Article  CAS  Google Scholar 

  27. Bullivant JP, Zhao S, Willenberg BJ et al (2013) Materials characterization of Feraheme/ferumoxytol and preliminary evaluation of its potential for magnetic fluid hyperthermia. Int J Mol Sci 14:17501–17510

    Article  PubMed  PubMed Central  Google Scholar 

  28. Neuwelt EA, Hamilton BE, Varallyay CG et al (2009) Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)? Kidney Int 75:465–474

    Article  CAS  PubMed  Google Scholar 

  29. Haas M, Sis B, Racusen LC et al (2014) Banff 2013 meeting report: inclusion of C4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant 14:272–283

    Article  CAS  PubMed  Google Scholar 

  30. Yang D, Ye Q, Williams M et al (2001) USPIO-enhanced dynamic MRI: evaluation of normal and transplanted rat kidneys. Magn Reson Med 46:1152–1163

    Article  CAS  PubMed  Google Scholar 

  31. Ye Q, Yang D, Williams M et al (2002) In vivo detection of acute rat renal allograft rejection by MRI with USPIO particles. Kidney Inter 61:1124–1135

    Article  Google Scholar 

  32. McCullough BJ, Kolokythas O, Maki JH, Green DE (2013) Ferumoxytol in clinical practice: implications for MRI. J Magn Reson Imaging 37:1476–1479

    Article  PubMed  Google Scholar 

  33. Bashir MR, Bhatti L, Marin D, Nelson RC (2015) Emerging applications for ferumoxytol as a contrast agent in MRI. J Magn Reson Imaging 41:884–898

    Article  PubMed  Google Scholar 

  34. Pai A, Nielsen J, Kausz A et al (2010) Plasma pharmacokinetics of two consecutive doses of ferumoxytol in healthy subjects. Clin Pharmacol Therap 88:237–242

    Article  CAS  Google Scholar 

  35. Auerbach M, Ballard H (2010) Clinical use of intravenous iron: administration, efficacy, and safety. ASH Educ Program Book 2010:338–347

    Google Scholar 

  36. Thoeny HC, Zumstein D, Simon-Zoula S et al (2006) Functional evaluation of transplanted kidneys with diffusion-weighted and BOLD MR imaging: initial experience 1. Radiology 241:812–821

    Article  PubMed  Google Scholar 

  37. Sadowski EA, Djamali A, Wentland AL et al (2010) Blood oxygen level-dependent and perfusion magnetic resonance imaging: detecting differences in oxygen bioavailability and blood flow in transplanted kidneys. Magn Reson Imaging 28:56–64

    Article  PubMed  Google Scholar 

  38. Khalifa F, Abou El-Ghar M, Abdollahi B et al (2013) A comprehensive non-invasive framework for automated evaluation of acute renal transplant rejection using DCE-MRI. NMR Biomed 26:1460–1470

    Article  PubMed  Google Scholar 

  39. Sharma RK, Gupta RK, Poptani H et al (1995) The magnetic resonance renogram in renal transplant evaluation using dynamic contrast-enhanced MR imaging. Transplantation 59:1405–1409

    Article  CAS  PubMed  Google Scholar 

  40. Xiao W, Xu J, Wang Q et al (2012) Functional evaluation of transplanted kidneys in normal function and acute rejection using BOLD MR imaging. Eur J Radiol 81:838–845

    Article  PubMed  Google Scholar 

  41. Vermathen P, Binser T, Boesch C et al (2012) Three-year follow-up of human transplanted kidneys by diffusion-weighted MRI and blood oxygenation level-dependent imaging. J Magn Reson Imaging 35:1133–1138

    Article  PubMed  Google Scholar 

  42. Park SY, Kim CK, Park BK et al (2012) Evaluation of transplanted kidneys using blood oxygenation level–dependent MRI at 3 T: a preliminary study. Am J Roentgenol 198:1108–1114

    Article  Google Scholar 

  43. Xin-Long P, Jing-Xia X, Jian-Yu L et al (2012) A preliminary study of blood-oxygen-level-dependent MRI in patients with chronic kidney disease. Magn Reson Imaging 30:330–335

    Article  PubMed  Google Scholar 

  44. Djamali A, Sadowski EA, Samaniego-Picota M et al (2006) Noninvasive assessment of early kidney allograft dysfunction by blood oxygen level-dependent magnetic resonance imaging. Transplantation 82:621–628

    Article  PubMed  Google Scholar 

  45. Djamali A, Sadowski EA, Muehrer RJ et al (2007) BOLD-MRI assessment of intrarenal oxygenation and oxidative stress in patients with chronic kidney allograft dysfunction. Am J Physiol Renal Physiol 292:F513–F522

    Article  CAS  PubMed  Google Scholar 

  46. Sadowski EA, Fain SB, Alford SK et al (2005) Assessment of acute renal transplant rejection with blood oxygen level–dependent MR imaging: initial experience 1. Radiology 236:911–919

    Article  PubMed  Google Scholar 

  47. Bujok GJ, Misio ek H (2006) Choice of optimal anesthesia for transdermal kidney biopsy. Pediatr Anesth 16:596–597

    Article  Google Scholar 

  48. Benfield MR, Herrin J, Feld L et al (1999) SAFETY OF KIDNEY BIOPSY IN PEDIATRIC TRANSPLANTATION: a report of the controlled clinical trials in pediatric transplantation trial of induction therapy study Group1, 2. Transplantation 67:544–547

    Article  CAS  PubMed  Google Scholar 

  49. Donati-Bourne J, Roberts H, Coleman R (2014) Donor-recipient size mismatch in paediatric renal transplantation. J Transp Secur 67:544–547

    Google Scholar 

  50. Bunchman TE, Fryd DS, Sibley RK, Mauer SM (1990) Manifestations of renal allograft rejection in small children receiving adult kidneys. Pediatr Nephrol 4:255–258

    Article  CAS  PubMed  Google Scholar 

  51. Bergler T, Jung B, Bourier F et al (2016) Infiltration of macrophages correlates with severity of allograft rejection and outcome in human kidney transplantation. PLoS One 11:e0156900

    Article  PubMed  PubMed Central  Google Scholar 

  52. Wyburn KR, Jose MD, Wu H et al (2005) The role of macrophages in allograft rejection. Transplantation 80:1641–1647

    Article  PubMed  Google Scholar 

  53. Mannon RB (2012) Macrophages: contributors to allograft dysfunction, repair or innocent bystanders? Curr Opin Organ Transplant 17:20–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chadban SJ, Wu H, Hughes J (2010) Macrophages and kidney transplantation. Semin Nephrol 30:278–289

    Article  CAS  PubMed  Google Scholar 

  55. Shushakova N, Skokowa J, Schulman J et al (2002) C5a anaphylatoxin is a major regulator of activating versus inhibitory FcγRs in immune complex–induced lung disease. J Clin Invest 110:1823–1830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhang Y, Dodd SJ, Hendrich KS et al (2000) Magnetic resonance imaging detection of rat renal transplant rejection by monitoring macrophage infiltration. Kidney Int 58:1300–1310

    Article  CAS  PubMed  Google Scholar 

  57. Beckmann N, Cannet C, Fringeli-Tanner M et al (2003) Macrophage labeling by SPIO as an early marker of allograft chronic rejection in a rat model of kidney transplantation. Magn Reson Med 49:459–467

    Article  CAS  PubMed  Google Scholar 

  58. Beckmann N, Cannet C, Zurbruegg S et al (2006) Macrophage infiltration detected at MR imaging in rat kidney allografts: early marker of chronic rejection? Radiology 240:717–724

    Article  PubMed  Google Scholar 

  59. Dempster W (1971) The nature of experimental second-set kidney transplant reaction: 2. The mimicking of the haemodynamic upset by pharmacological and other means. Br J Exper Pathol 52:172

    CAS  Google Scholar 

  60. Salaman J, Griffin PA (1983) Fine-needle intrarenal manometry: a new test for rejection in cyclosporin-treated recipients of kidney transplants. Lancet 322:709–711

    Article  Google Scholar 

  61. Lu M, Cohen MH, Rieves D, Pazdur R (2010) FDA report: ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease. Am J Hematol 85:315–319

    CAS  PubMed  Google Scholar 

  62. Golovko D, Sutton E, Daldrup-Link HE (2013) Magnetic resonance imaging of the Bone Marrow contrast Media for Bone Marrow Imaging. Magn Reson Imaging Bone Marrow. doi:10.1007/174-2012-577

    Google Scholar 

  63. McDonald RJ, McDonald JS, Kallmes DF et al (2015) Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 275:772–782

    Article  PubMed  Google Scholar 

  64. Heelan BT, Osman S, Blyth A et al (1998) Use of 2-[18F]fluoro-2-deoxyglucose as a potential agent in the prediction of graft rejection by positron emission tomography. Transplantation 66:1101–1103

    Article  CAS  PubMed  Google Scholar 

  65. Kuyama J, McCormack A, George AJ et al (1997) Indium-111 labelled lymphocytes: isotope distribution and cell division. Eur J Nucl Med 24:488–496

    CAS  PubMed  Google Scholar 

  66. Thölking G, Schuette-Nuetgen K, Kentrup D, Pawelski H, Reuter S (2016) Imaging-based diagnosis of acute renal allograft rejection. World J Transplant 6:174–182

    Article  PubMed  PubMed Central  Google Scholar 

  67. George AJ, Bhakoo KK, Haskard DO et al (2006) Imaging molecular and cellular events in transplantation. Transplantation 82:1124–1129

    Article  CAS  PubMed  Google Scholar 

  68. Ho C, Hitchens TK (2004) A non-invasive approach to detecting organ rejection by MRI: monitoring the accumulation of immune cells at the transplanted organ. Curr Pharm Biotechnol 5:551–566

    Article  CAS  PubMed  Google Scholar 

  69. Kondo I, Ohmori K, Oshita A et al (2004) Leukocyte-targeted myocardial contrast echocardiography can assess the degree of acute allograft rejection in a rat cardiac transplantation model. Circulation 109:1056–1061

    Article  PubMed  Google Scholar 

  70. Dodd CH, Hsu HC, Chu WJ et al (2001) Normal T-cell response and in vivo magnetic resonance imaging of T cells loaded with HIV transactivator-peptide-derived superparamagnetic nanoparticles. J Immunol Methods 256:89–105

    Article  CAS  PubMed  Google Scholar 

  71. Weller GE, Lu E, Csikari MM et al (2003) Ultrasound imaging of acute cardiac transplant rejection with microbubbles targeted to intercellular adhesion molecule-1. Circulation 108:218–224

    Article  PubMed  Google Scholar 

  72. Nilsson L, Ekberg H, Fält K et al (1994) Renal arteriovenous shunting in rejecting allograft, hydronephrosis, or haemorrhagic hypotension in the rat. Nephrol Dial Transplant 9:1634–1639

    CAS  PubMed  Google Scholar 

  73. Nilsson L, Sterner G, Ekberg H (1999) Presence of arteriovenous shunting in transplanted but not in native single kidney in the rat. Scand J Urol Nephrol 33:363–367

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a Transdisciplinary Initiatives Program Grant from the Child Health Research Institute at Stanford University. We would like to thank Kevin Epperson, Anne Sawyer, Allan White, and Mark Datuin for help with ferumoxytol administrations and MRI scans.

Author information

Authors and Affiliations

  1. Department of Radiology, Pediatric Molecular Imaging in the Molecular Imaging Program at Stanford (@PedsMIPS), Lucile Packard Children’s Hospital, Stanford University School of Medicine, 725 Welch Road, Stanford, 94305, CA, USA

    Maryam Aghighi, Laura Pisani, Ashok J. Theruvath, Anne M. Muehe, Jessica Donig, Ramsha Khan, Samantha J. Holdsworth & Heike E. Daldrup-Link

  2. Department of Pathology, Stanford University, Stanford, CA, USA

    Neeraja Kambham

  3. Department of Surgery, Stanford University, Stanford, CA, USA

    Waldo Concepcion

  4. Department of Pediatrics, Stanford University, Stanford, CA, USA

    Paul C. Grimm

  5. Department of Pediatrics, Lucile Packard Children’s Hospital, Stanford School of Medicine, 725 Welch Rd, Stanford, CA, 94305, USA

    Heike E. Daldrup-Link

Authors
  1. Maryam Aghighi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura Pisani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ashok J. Theruvath
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne M. Muehe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jessica Donig
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ramsha Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Samantha J. Holdsworth
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Neeraja Kambham
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Waldo Concepcion
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Paul C. Grimm
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Heike E. Daldrup-Link
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.D.L. conceived the idea and designed the study. J.D., A.M., P.G., and M.A. coordinated clinical studies. L.P. and S.H. optimized the MR imaging protocol. H.D.L, M.A., S.H., L.P., and J.D. performed MRI data analysis. J.D and N.K. performed histopathological experiments. H.D.L. drafted the manuscript. M.A, A.T., P.G., R.K., W.C., and L.P. edited and completed the draft. All other authors approved the final version.

Corresponding author

Correspondence to Heike E. Daldrup-Link.

Ethics declarations

This HIPAA compliant study was approved by the committee on human research at our institution and was performed under an investigator-initiated investigational new drug (IND) approval with the FDA after written informed consent was obtained from the child’s legal representative or the competent adult patient (Clinical Trials Identifier: NCT02006108).

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

ESM 1

(PDF 257 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aghighi, M., Pisani, L., Theruvath, A.J. et al. Ferumoxytol Is Not Retained in Kidney Allografts in Patients Undergoing Acute Rejection. Mol Imaging Biol 20, 139–149 (2018). https://doi.org/10.1007/s11307-017-1084-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-017-1084-8

Key words

Search

Navigation