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