Molecular Imaging and Biology

, Volume 20, Issue 1, pp 139–149 | Cite as

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

  • Maryam Aghighi
  • Laura Pisani
  • Ashok J. Theruvath
  • Anne M. Muehe
  • Jessica Donig
  • Ramsha Khan
  • Samantha J. Holdsworth
  • Neeraja Kambham
  • Waldo Concepcion
  • Paul C. Grimm
  • Heike E. Daldrup-LinkEmail author
Research Article



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


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.


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).


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.

Key words

Kidney allograft rejection MR imaging Iron oxide nanoparticles Ferumoxytol 



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 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.

Compliance with Ethical Standards

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.

Supplementary material

11307_2017_1084_MOESM1_ESM.pdf (258 kb)
ESM 1 (PDF 257 kb)


  1. 1.
    Thiruchelvam PT, Willicombe M, Hakim N et al (2011) Renal transplantation. Br Med J 343:d7300CrossRefGoogle Scholar
  2. 2.
    Magee JC, Bucuvalas JC, Farmer DG et al (2004) Pediatric transplantation. Am J Transplant 4(Suppl 9):54–71CrossRefPubMedGoogle Scholar
  3. 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 326:1727–1732CrossRefPubMedGoogle Scholar
  4. 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 214:795–800CrossRefPubMedGoogle Scholar
  5. 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 36:2664–2667CrossRefPubMedGoogle Scholar
  6. 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 36:2997–3001CrossRefGoogle Scholar
  7. 7.
    Cosgrove DO, Chan KE (2008) Renal transplants: what ultrasound can and cannot do. Ultrasound Q 24:77–87CrossRefPubMedGoogle Scholar
  8. 8.
    Bashir MR, Jaffe TA, Brennan TV et al (2013) Renal transplant imaging using magnetic resonance angiography with a nonnephrotoxic contrast agent. Transplantation 96:91–96CrossRefPubMedGoogle Scholar
  9. 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 16:1077–1085CrossRefPubMedPubMedCentralGoogle Scholar
  10. 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–c57CrossRefPubMedGoogle Scholar
  11. 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):727–735CrossRefGoogle Scholar
  12. 12.
    Kalb B, Martin DR, Salman K et al (2008) Kidney transplantation: structural and functional evaluation using MR Nephro-urography. J Magnet Reson Imaging 28:805–822CrossRefGoogle Scholar
  13. 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 6:965–973CrossRefPubMedGoogle Scholar
  14. 14.
    Kriz J, Jirák D, Girman P et al (2005) Magnetic resonance imaging of pancreatic islets in tolerance and rejection. Transplantation 80:1596–1603CrossRefPubMedGoogle Scholar
  15. 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 256:847–854CrossRefPubMedGoogle Scholar
  16. 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 17:2898–2907CrossRefGoogle Scholar
  17. 17.
    Ricardo SD, van Goor H, Eddy AA (2008) Macrophage diversity in renal injury and repair. J Clin Invest 118:3522–3530CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Magil AB (2009) Monocytes/macrophages in renal allograft rejection. Transplant Rev 23:199–208CrossRefGoogle Scholar
  19. 19.
    Tinckam KJ, Djurdjev O, Magil AB (2005) Glomerular monocytes predict worse outcomes after acute renal allograft rejection independent of C4d status. Kidney Int 68:1866–1874CrossRefPubMedGoogle Scholar
  20. 20.
    Corot C, Robert P, Idee JM, Port M (2006) Recent advances in iron oxide nanocrystal technology for medical imaging. Adv Drug Deliv Rev 58:1471–1504CrossRefPubMedGoogle Scholar
  21. 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 17:5695–5704CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Aghighi M, Golovko D, Ansari C et al (2015) Imaging tumor necrosis with Ferumoxytol. PLoS One 10:e0142665CrossRefPubMedPubMedCentralGoogle Scholar
  23. 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 51:221–227CrossRefGoogle Scholar
  24. 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 55:622–627CrossRefGoogle Scholar
  25. 25.
    AMAG Pharmaceuticals, Inc. (2009) Feraheme (ferumoxytol) package insert. Lexington, MAGoogle Scholar
  26. 26.
    Balakrishnan VS, Rao M, Kausz AT et al (2009) Physicochemical properties of ferumoxytol, a new intravenous iron preparation. Eur J Clin Investig 39:489–496CrossRefGoogle Scholar
  27. 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 14:17501–17510CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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 75:465–474CrossRefPubMedGoogle Scholar
  29. 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 14:272–283CrossRefPubMedGoogle Scholar
  30. 30.
    Yang D, Ye Q, Williams M et al (2001) USPIO-enhanced dynamic MRI: evaluation of normal and transplanted rat kidneys. Magn Reson Med 46:1152–1163CrossRefPubMedGoogle Scholar
  31. 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 61:1124–1135CrossRefGoogle Scholar
  32. 32.
    McCullough BJ, Kolokythas O, Maki JH, Green DE (2013) Ferumoxytol in clinical practice: implications for MRI. J Magn Reson Imaging 37:1476–1479CrossRefPubMedGoogle Scholar
  33. 33.
    Bashir MR, Bhatti L, Marin D, Nelson RC (2015) Emerging applications for ferumoxytol as a contrast agent in MRI. J Magn Reson Imaging 41:884–898CrossRefPubMedGoogle Scholar
  34. 34.
    Pai A, Nielsen J, Kausz A et al (2010) Plasma pharmacokinetics of two consecutive doses of ferumoxytol in healthy subjects. Clin Pharmacol Therap 88:237–242CrossRefGoogle Scholar
  35. 35.
    Auerbach M, Ballard H (2010) Clinical use of intravenous iron: administration, efficacy, and safety. ASH Educ Program Book 2010:338–347Google Scholar
  36. 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 241:812–821CrossRefPubMedGoogle Scholar
  37. 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 28:56–64CrossRefPubMedGoogle Scholar
  38. 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 26:1460–1470CrossRefPubMedGoogle Scholar
  39. 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 59:1405–1409CrossRefPubMedGoogle Scholar
  40. 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 81:838–845CrossRefPubMedGoogle Scholar
  41. 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 35:1133–1138CrossRefPubMedGoogle Scholar
  42. 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 198:1108–1114CrossRefGoogle Scholar
  43. 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 30:330–335CrossRefPubMedGoogle Scholar
  44. 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 82:621–628CrossRefPubMedGoogle Scholar
  45. 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–F522CrossRefPubMedGoogle Scholar
  46. 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 236:911–919CrossRefPubMedGoogle Scholar
  47. 47.
    Bujok GJ, Misio ek H (2006) Choice of optimal anesthesia for transdermal kidney biopsy. Pediatr Anesth 16:596–597CrossRefGoogle Scholar
  48. 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 67:544–547CrossRefPubMedGoogle Scholar
  49. 49.
    Donati-Bourne J, Roberts H, Coleman R (2014) Donor-recipient size mismatch in paediatric renal transplantation. J Transp Secur 67:544–547Google Scholar
  50. 50.
    Bunchman TE, Fryd DS, Sibley RK, Mauer SM (1990) Manifestations of renal allograft rejection in small children receiving adult kidneys. Pediatr Nephrol 4:255–258CrossRefPubMedGoogle Scholar
  51. 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:e0156900CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Wyburn KR, Jose MD, Wu H et al (2005) The role of macrophages in allograft rejection. Transplantation 80:1641–1647CrossRefPubMedGoogle Scholar
  53. 53.
    Mannon RB (2012) Macrophages: contributors to allograft dysfunction, repair or innocent bystanders? Curr Opin Organ Transplant 17:20–25CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Chadban SJ, Wu H, Hughes J (2010) Macrophages and kidney transplantation. Semin Nephrol 30:278–289CrossRefPubMedGoogle Scholar
  55. 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 110:1823–1830CrossRefPubMedPubMedCentralGoogle Scholar
  56. 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 58:1300–1310CrossRefPubMedGoogle Scholar
  57. 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 49:459–467CrossRefPubMedGoogle Scholar
  58. 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 240:717–724CrossRefPubMedGoogle Scholar
  59. 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 52:172Google Scholar
  60. 60.
    Salaman J, Griffin PA (1983) Fine-needle intrarenal manometry: a new test for rejection in cyclosporin-treated recipients of kidney transplants. Lancet 322:709–711CrossRefGoogle Scholar
  61. 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 85:315–319PubMedGoogle Scholar
  62. 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. 63.
    McDonald RJ, McDonald JS, Kallmes DF et al (2015) Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 275:772–782CrossRefPubMedGoogle Scholar
  64. 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 66:1101–1103CrossRefPubMedGoogle Scholar
  65. 65.
    Kuyama J, McCormack A, George AJ et al (1997) Indium-111 labelled lymphocytes: isotope distribution and cell division. Eur J Nucl Med 24:488–496PubMedGoogle Scholar
  66. 66.
    Thölking G, Schuette-Nuetgen K, Kentrup D, Pawelski H, Reuter S (2016) Imaging-based diagnosis of acute renal allograft rejection. World J Transplant 6:174–182CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    George AJ, Bhakoo KK, Haskard DO et al (2006) Imaging molecular and cellular events in transplantation. Transplantation 82:1124–1129CrossRefPubMedGoogle Scholar
  68. 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 5:551–566CrossRefPubMedGoogle Scholar
  69. 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 109:1056–1061CrossRefPubMedGoogle Scholar
  70. 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 256:89–105CrossRefPubMedGoogle Scholar
  71. 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 108:218–224CrossRefPubMedGoogle Scholar
  72. 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 9:1634–1639PubMedGoogle Scholar
  73. 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 33:363–367CrossRefPubMedGoogle Scholar

Copyright information

© World Molecular Imaging Society 2017

Authors and Affiliations

  • Maryam Aghighi
    • 1
  • Laura Pisani
    • 1
  • Ashok J. Theruvath
    • 1
  • Anne M. Muehe
    • 1
  • Jessica Donig
    • 1
  • Ramsha Khan
    • 1
  • Samantha J. Holdsworth
    • 1
  • Neeraja Kambham
    • 2
  • Waldo Concepcion
    • 3
  • Paul C. Grimm
    • 4
  • Heike E. Daldrup-Link
    • 1
    • 5
    Email author
  1. 1.Department of Radiology, Pediatric Molecular Imaging in the Molecular Imaging Program at Stanford (@PedsMIPS)Lucile Packard Children’s Hospital, Stanford University School of MedicineStanfordUSA
  2. 2.Department of PathologyStanford UniversityStanfordUSA
  3. 3.Department of SurgeryStanford UniversityStanfordUSA
  4. 4.Department of PediatricsStanford UniversityStanfordUSA
  5. 5.Department of PediatricsLucile Packard Children’s Hospital, Stanford School of MedicineStanfordUSA

Personalised recommendations