Imaging Kidney Transplant Rejection Using Ferumoxytol-Enhanced Magnetic Resonance

• ClinicalTrials.gov Identifier: NCT02006108
• Recruitment Status: Completed
• First Posted: December 9, 2013
• Results First Posted: June 27, 2017
• Last Update Posted: May 11, 2018
• Sponsor: Stanford University
• Collaborator: Lucile Packard Children's Hospital
• Information provided by (Responsible Party): Heike E Daldrup-Link, Stanford University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Renal Transplant Rejection	Drug: Feraheme; Other: MRI-GE Healthcare 3 Tesla magnet	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Non-invasive MR Imaging Diagnosis of Transplant Rejection
• Actual Study Start Date: November 27, 2012
• Actual Primary Completion Date: April 11, 2017
• Actual Study Completion Date: April 11, 2017

Arms and Interventions

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 Name: Ferumoxytol; Other: MRI-GE Healthcare 3 Tesla magnet; All patients will undergo; Other Names: Magnetic Resonance Imaging; MR Imaging

Outcome Measures

Primary Outcome Measures :

1. Radiologically Detectable Differences in Signal Intensity Between Healthy and Rejected Kidneys, Measured Using T2* Maps [ Time Frame: 24 hours to 7 days ]
   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.

Secondary Outcome Measures :

1. Correlation of Cell-bound Iron Quantities on QSM Sequences With Macrophage and Iron Stains on Histopathology [ Time Frame: 3 weeks ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 8 Years to 40 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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.

Contacts and Locations

Locations

United States, California

Lucile Packard Children's Hospital

Stanford, California, United States, 94305

Sponsors and Collaborators

Stanford University

Lucile Packard Children's Hospital

Investigators

• Principal Investigator: Heike E Daldrup-Link, MD, PhD; Stanford University

  Study Documents (Full-Text)

Documents provided by Heike E Daldrup-Link, Stanford University:

Study Protocol  [PDF] November 30, 2016

Statistical Analysis Plan  [PDF] April 6, 2018

More Information

• Responsible Party: Heike E Daldrup-Link, Principle Investigator, Stanford University
• ClinicalTrials.gov Identifier: NCT02006108
• Other Study ID Numbers: 94027
• First Posted: December 9, 2013
• Results First Posted: June 27, 2017
• Last Update Posted: May 11, 2018
• Last Verified: April 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Heike E Daldrup-Link, Stanford University:

kidney; transplant; rejection; Feraheme; ferumoxytol

Additional relevant MeSH terms:

Ferrosoferric Oxide; Hematinics; Parenteral Nutrition Solutions; Pharmaceutical Solutions