Renal Allograft Fibrosis Study

Characterization of Renal Allograft Fibrosis and Prediction of Outcome Using a Quantitative MRI Approach

Despite the reduction in acute rejection episodes in renal transplant patients due to modern immunosuppression, proportionate improvements in long-term allograft survival have not been achieved. Virtually any disease or injury affecting renal allografts can culminate in irreversible injury of tubular epithelial cells and the development of interstitial fibrosis and tubular atrophy (IFTA). Renal allograft fibrosis drives chronic kidney disease (CKD) progression, predicts allograft failure and is associated with increased patient mortality. Other prognostic and/or actionable diagnoses described by the pathologic Banff scheme, such as inflammation, often co-exist and contribute to IFTA. Immune cell infiltration within allografts and within areas of IFTA (i-IFTA) can drive progressive kidney injury, fibrosis and worsened outcome. Pathology is the reference standard for IFTA; however, allograft biopsy has many well-known limitations and is not an ideal method for monitoring patients during trials of new therapies aimed at improving allograft survival. There is an urgent and unmet need for non-invasive assessment of renal allograft IFTA.

Multiparametric MRI (mpMRI), including relaxometry [the spin-lock relaxation time T1ρ, a marker of interaction of water with macromolecules in tissues; the spin-lattice relaxation time T1, a marker of interstitial edema and collagen volume fraction)] and advanced diffusion [intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI), a marker of diffusion and perfusion] provides insight into renal structure and function. Validation of advanced MRI methods as markers of renal allograft IFTA would be of major clinical significance to enable early detection, assess the efficacy of novel anti-fibrotic agents, and provide longitudinal disease monitoring. The study team has established proof-of-concept in renal allografts with stable function and IFTA without confounding rejection or infection that mpMRI techniques are feasible for measuring fibrosis, especially using the combination of T1 and DWI. The study has established that urinary biomarkers for renal allograft fibrosis are also promising and have been validated against pathology in initial studies.

In this proposal, the researchers will develop a short, non-contrast multiparametric MRI (mpMRI) protocol, consisting of advanced relaxometry (T1 mapping and T1ρ) and advanced diffusion weighted imaging (IVIM-DWI) to accurately detect and stage allograft fibrosis, taking into account confounding Banff variables of inflammation and tested against biopsy. The researchers will also assess the added value of urinary biomarkers of IFTA and if successful, this study will benefit a large population of patients with renal allograft fibrosis in the United States, enabling early diagnosis, optimized treatment planning, prognostication and longitudinal disease monitoring.

Study Overview

• Status: Enrolling by invitation
• Conditions: Renal Allograft Fibrosis

• Study Type: Observational
• Enrollment (Estimated): 162

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10021
      • Weill Cornell Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Patients with diagnosed renal allograft fibrosis.

Description

Inclusion Criteria:

• Patients post renal transplantation, with acute or chronic allograft dysfunction, referred for biopsy based on clinical grounds (indication biopsy). Patients with be considered to have allograft dysfunction if: 1. Patients will be considered to have acute allograft dysfunction if there is a 15% decline in eGFR or a 0.3-mg/dL increase in sCr level, with laboratory and clinical findings that exclude pre-renal or post-renal dysfunction. 2. Patients will be considered to have chronic allograft dysfunction if there is a sustained >50% increase in sCr/decrease in eGFR (over their post-transplant nadir creatinine), occurring over a period of >3 months, with laboratory and clinical findings that exclude pre-renal or post-renal dysfunction.
• Patients with stable allograft function and donor-specific antibody (DSA) positivity, referred for surveillance biopsy at 3 and 12 months post transplantation. Patients with be considered to have stable allograft function if: 1. Patients will be considered to have chronic stable allograft function if they have a stable eGFR > 45 ml/min & a spot urine protein:creatinine ratio < 0.2; 2. Stable creatinine/eGFR (i.e. <25% change in serum creatinine (Cr) and/or eGFR from post transplant baseline).
• Patient is able to give informed consent for this study.
• Study team will recruit patients after 1 month post-transplant period since the early post transplant course is associated with increased risk of acute dysfunction (i.e. acute tubular necrosis or acute rejection episodes).
• Healthy volunteers with no renal disease will be recruited for protocol optimization and to serve as controls.
• Potential renal donors undergoing clinical non-contrast or contrast-enhanced MRI will be recruited to serve as controls.

Exclusion Criteria:

• Age less than 18 years.
• Renal transplantation <1 month prior to scanning.
• Evidence of large vessel or urinary tract complication of the renal transplant.
• Unable or unwilling to give informed consent.

• Contra-indications to MRI

  1. Electrical implants such as cardiac pacemakers or perfusion pumps.
  2. Ferromagnetic implants such as aneurysm clips, surgical clips, prostheses, artificial hearts, valves with steel parts, metal fragments, shrapnel, tattoos near the eye, or steel implants.
  3. Ferromagnetic objects such as jewelry or metal clips in clothing.
  4. Pregnant subjects.
  5. Pre-existing medical conditions including a likelihood of developing seizures or claustrophobic reactions.

The inclusion and exclusion criteria are identical at ISMMS and WCMC.

• Screening for eligibility will be performed by the transplant nephrology team at both centers. Data relevant to eligibility will be reviewed, including age, presence of allograft dysfunction and its ascertainment (clinical, laboratory and prior biopsy data), and MRI safety will also be reviewed by the study coordinator.
• There are no exclusions based on race, sex/gender, preferred language.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Renal transplant patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of renal allograft fibrosis	Detection of the presence of renal allograft fibrosis using MRI in patients undergoing biopsies.	2 weeks after renal allograft biopsy
Banff scoring system for fibrosis	Detection of the severity of renal allograft fibrosis using MRI in patients undergoing biopsies, using the Banff scoring system for interstitial fibrosis (ci) + tubular atrophy (ct); each subscore from 0-3 with full range from 0-6, higher score indicates higher severity).	2 weeks after renal allograft biopsy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of renal allograft inflammation	Detection of the presence of renal allograft inflammation using MRI in patients undergoing biopsies.	2 weeks after renal allograft biopsy
Banff scoring system for inflammation	Detection of the severity of renal allograft inflammation using MRI in patients undergoing biopsies using the Banff scoring system. the Banff lesion scored include inflammation in the area of IFTA (i-IFTA), tubulitis (t), glomerular basement membrane (GBM) double contours (cg), vascular fibrous intimal thickening (cv), glomerulitis (g), intimal arteritis (v), and peritubular capillaritis (ptc), all subscores range, 0-3, with full range 0-3, higher score indicating higher severity.	2 weeks after renal allograft biopsy
4-gene fibrosis signature score	4-gene fibrosis signature score as a measurement of urinary mRNA (which consists of CDH1 mRNA, SLC12A1 mRNA, Vim mRNA and 18S rRNA) obtained from urine cells for the detection of renal allograft fibrosis. Measurement is a continuous scale with no maximum, higher score indicates higher severity.	Within 1 year of urine processing
3-gene inflammation score	3-gene inflammation score as a measurement of urinary mRNA (which consists of CD3 mRNA, CXCL10 mRNA, and 18S rRNA) obtained from urine cells for the detection of renal allograft inflammation. Measurement is a continuous scale with no maximum, higher score indicates higher severity.	Within 1 year of urine processing
Change in estimated Glomerular filtration rate (eGFR)	Renal function assessed by estimated Glomerular filtration rate (eGFR) which is a test used to check how well the kidneys are working. Specifically, it estimates how much blood passes through the glomeruli each minute. Glomeruli are the tiny filters in the kidneys that filter waste from the blood.	Baseline and within 2 years after initial MRI
Change in Protein level in urine	Renal function assessed by protein level in urine to detect proteinuria. Proteinuria is defined as (>1 g/dL).	Baseline and within 2 years after initial MRI
Change in Interstitial fibrosis and tubular atrophy (IFTA) stage	Renal function assessed by change in IFTA stage as determined by the Banff scoring system. The Banff lesion score include interstitial fibrosis (ci) + tubular atrophy (ct). Each subscore range 0-3, with total range from 0-6 and a higher score indicates higher severity.	Within 2 years after initial MRI

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Weill Medical College of Cornell University
• Investigators: Principal Investigator: Octavia Bane, PhD, Icahn School of Medicine at Mount Sinai; Principal Investigator: Sara Lewis, MD, Icahn School of Medicine at Mount Sinai

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2022
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: September 16, 2021
• First Submitted That Met QC Criteria: September 16, 2021
• First Posted (Actual): September 27, 2021

Study Record Updates

• Last Update Posted (Estimated): July 1, 2025
• Last Update Submitted That Met QC Criteria: June 26, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: MRI; Chronic Kidney Disease; Transplant; Kidney; Renal allograft fibrosis
• Additional Relevant MeSH Terms: Pathologic Processes; Fibrosis
• Other Study ID Numbers: GCO 20-2690; R01DK129888 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Not encompassed in the grant proposal to share data with others outside of this study.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No