Clinical trial NCT05058170: Renal Allograft Fibrosis Study
Official title: Characterization of Renal Allograft Fibrosis and Prediction of Outcome Using a Quantitative MRI Approach
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: Renal Allograft Fibrosis
Keywords: Renal allograft fibrosis
Kidney
Chronic Kidney Disease
Transplant
MRI
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: Weill Medical College of Cornell University
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2021-09-27
Enrollment: 280
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients with diagnosed renal allograft fibrosis.

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Presence of renal allograft fibrosis
timeFrame: 2 weeks after renal allograft biopsy
measure: Banff scoring system for fibrosis
timeFrame: 2 weeks after renal allograft biopsy
Secondary outcomes:
measure: Presence of renal allograft inflammation
timeFrame: 2 weeks after renal allograft biopsy
measure: Banff scoring system for inflammation
timeFrame: 2 weeks after renal allograft biopsy
measure: 4-gene fibrosis signature score
timeFrame: Within 1 year of urine processing
measure: 3-gene inflammation score
timeFrame: Within 1 year of urine processing
measure: Change in estimated Glomerular filtration rate (eGFR)
timeFrame: Baseline and within 2 years after initial MRI
measure: Change in Protein level in urine
timeFrame: Baseline and within 2 years after initial MRI
measure: Change in Interstitial fibrosis and tubular atrophy (IFTA) stage
timeFrame: Within 2 years after initial MRI
Other outcomes:
Locations:
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Sara Lewis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Icahn School of Medicine at Mount Sinai
name: Octavia Bane, PhD
role: PRINCIPAL_INVESTIGATOR
References: