Imaging Kidney Transplant Rejection Using Ferumoxytol-Enhanced Magnetic Resonance

Non-invasive MR Imaging Diagnosis of Transplant Rejection

The goal of this study is to develop a non-invasive imaging test for in vivo detection of kidney transplant rejection. The hypotheses are that 1) Ferumoxytol-MRI can generate accurate estimates of tissue iron concentrations and tissue macrophages. 2) The signal given by a renal allograft on Ferumoxytol-MRI demonstrates significant differences between rejected and non-rejected transplants.

Study Overview

• Status: Completed
• Conditions: Renal Transplant Rejection
• Intervention / Treatment: Drug: Feraheme; Other: MRI-GE Healthcare 3 Tesla magnet

Detailed Description

In children with kidney transplants, immunologically mediated rejection is the major cause of allograft failure. Thus, the therapeutic success of kidney transplants is highly dependent on the ability to avoid rejection during both the acute and chronic phase after transplantation. Children with kidney transplants currently undergo at least three routine (protocol) biopsies during the first two years after the transplantation in addition to biopsies required to investigate deterioration of kidney function. These biopsies are invasive and nearly always require general anesthesia, causing anxiety and distress of the patients and their parents, as well as significant costs to our health care system. There is currently no non-invasive diagnostic tool capable of detecting rejection in vivo. Thus, the goal of this study is to develop a non-invasive imaging test for in vivo detection of kidney transplant rejection. The investigators propose to accomplish this goal by detecting macrophage infiltration in kidney transplants with iron oxide nanoparticle-enhanced MR imaging. Macrophages play a major role in transplant rejection. CD68-positive macrophages comprise approximately 50% of the infiltrating leukocyte population in renal allograft rejection, they co-localize with areas of tissue-damage and fibrosis, and are preponderant in more severe forms of rejection. The investigators hypothesize that iron oxide nanoparticle-enhanced MR imaging can detect differences in macrophage infiltrations in renal allografts undergoing rejection as opposed to allografts without significant rejection. This hypothesis is based on the bio-physical properties of intravenously injected superparamagnetic iron oxide nanoparticles, which are phagocytosed by tissue macrophages and cause strong signal effects on MR images.

The specific aims of the study are the following:

Aim #1. Technical Development of a Quantitative Susceptibility Mapping (QSM)-Sequence for in vivo MRI detection and quantification of iron oxide nanoparticle-labeled macrophages.This aim will focus on the technical development of Quantitative Susceptibility Mapping (QSM), a novel MR imaging pulse sequence that will be used to accurately quantify the tissue concentration of free ferumoxytol and ferumoxytol in macrophages in renal allografts. Based on pulse sequence optimizations of phantoms with known concentrations of free and cell-bound iron, we expect to generate accurate estimates of tissue iron concentrations and macrophages with the QSM-MRI method.

Aim #2. Detect rejection in kidney allografts with ferumoxytol-enhanced MRI. The investigators hypothesize that ferumoxytol can detect and quantify macrophages in kidney allografts, based upon the observation that iron oxide nanoparticles can be taken up by macrophages in malignant tumors. The investigators will evaluate the ability of ferumoxytol to map macrophage quantities in renal allografts, with histopathological correlation. We expect significantly higher ferumoxytol-MRI enhancement and macrophage quantities in rejected allografts compared to non-rejected allografts.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Lucile Packard Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 40 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Completed solid organ transplant with referral for transplant follow-up

Exclusion Criteria:

• Exclusion criteria comprise MR-incompatible metal implants, need of sedation (since an anesthesia is not supported by this), claustrophobia or hemosiderosis/hemochromatosis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Feraheme; Intravenous injection of Feraheme, 5 mg Fe/kg Interventions: Drug: Feraheme Procedure: MR Scan	Drug: Feraheme; Therapeutic classification: iron preparations. Use: Off-label use of ultrasmall paramagnetic iron nanoparticle as contrast agent for magnetic resonance imaging; Other Names: Ferumoxytol; Other: MRI-GE Healthcare 3 Tesla magnet; All patients will undergo; Other Names: MR Imaging; Magnetic Resonance Imaging

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiologically Detectable Differences in Signal Intensity Between Healthy and Rejected Kidneys, Measured Using T2* Maps	According to the study hypothesis, macrophage infiltration into rejected kidneys will be significantly greater than in healthy kidneys; since macrophages are expected to phagocytose injected iron, there should be a detectable difference in signal intensity between healthy and rejected organs. This can be evaluated using semiquantitative T2* maps.	24 hours to 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of Cell-bound Iron Quantities on QSM Sequences With Macrophage and Iron Stains on Histopathology	To evaluate our ability to quantify cell-bound iron using the novel QSM sequence, we use histopathological data showing 1) the iron content of renal tissue sampled, and 2) the level of macrophage infiltration of the renal tissue. We will perform iron and macrophage stains in biopsy tissues in order to determine this.	3 weeks

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: Lucile Packard Children's Hospital
• Investigators: Principal Investigator: Heike E Daldrup-Link, MD, PhD, Stanford University

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2012
• Primary Completion (Actual): April 11, 2017
• Study Completion (Actual): April 11, 2017

Study Registration Dates

• First Submitted: October 28, 2013
• First Submitted That Met QC Criteria: December 4, 2013
• First Posted (Estimate): December 9, 2013

Study Record Updates

• Last Update Posted (Actual): May 11, 2018
• Last Update Submitted That Met QC Criteria: April 10, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: transplant; rejection; kidney; Feraheme; ferumoxytol
• Additional Relevant MeSH Terms: Hematinics; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Ferrosoferric Oxide
• Other Study ID Numbers: 94027

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided