Renal Osteodystrophy Precision Medicine Project

Grants and Contracts Details

Description

Scope of Work Consortium Institution: Consortium Investigator: Hartmut Malluche, MD Proposed project dates: 10/01/2022-09/30/2024 Project Background and Need for Subaward Mitigation and prevention of morbidity and mortality due to renal osteodystrophy (ROD) is impeded by the lack of large-scale databases containing data from deep phenotyping of patients across the spectrum of ROD. This proposal aims to obtain robust and necessary preliminary data for our RC2 by assessing the variability and demonstrating the rigor and reliability of single nuclei sequencing in bone by simultaneous profiling of the transcriptome (using 3’ gene expression) and epigenome (using ATACseq) to deepen our understanding of how genes are expressed and regulated across different cells and ROD types and kidney disease stages. Successful completion of these studies represents a crucial milestone in the process of discovering new information regarding unrecognized bone changes that have severe clinical complications. These goals will be executed according to the requested budget, with Dr. Malluche’s role outlined below. Bone Biopsy Bone biopsy will be performed on the patients agreeing to participate to the study. Two tetracycline compounds (tetracycline hydrochloride and demeclocycline hydrochloride) will be used to distinguish timed bone labels. Tetracycline hydrochloride gives a yellow color and demeclocycline hydrochloride (Declomycin®, Lederle, Wayne, NJ), a golden-yellowish fluorescence under fluorescent light microscopy. The labeling schedule consists of a 2-day oral administration of demeclocycline hydrochloride (150 mg bid) followed by a drug-free interval of 10 days and subsequent oral administration of tetracycline hydrochloride (250 mg bid) for 4 days. The bone biopsy will be performed 2-4 days after the last tetracycline dose. This dosing regimen is adjusted for CKD-5D patients. The study coordinator will provide study participants with a calendar indicating the date of the bone biopsy and dates on which the compounds should be taken and call study participants on the respective dates to remind them to take the medication. The biopsy will be performed under sedation (or general anesthesia as deemed necessary by the UK anesthesiologist). Additional local anesthesia using lidocaine 1% will be used. Bone samples will be taken from the anterior iliac crest using a vertical approach. This biopsy technique has been used extensively in CKD patients and is rapid and minimally invasive with an acceptable degree of discomfort. Biospecimen Processing, Storage, and/or Shipment Two separate bone biopsy cores will be collected from each study patient. Bones samples will be collected for analysis by UK BDRL (to be received and analyzed by UK) and a separate bone sample for transcriptomic and epigenomic analyses (to be shipped from UK to Northwestern University). • Bone samples that are to be shipped will be flash frozen via liquid nitrogen immediately after biopsy collection and then sent to the UK Bone Diagnostic and Research Laboratory (BDRL). Bone samples will be stored at -80?C in the BDRL biorepository, room MN564. Samples are registered and organized via a database which is stored on a shared network drive and backed up nightly. The servers are protected by the UK Research firewall and are in climate-controlled rooms with emergency power backup and extreme fire protection. Bone biopsy samples to be shipped will be sent via overnight carrier on dry ice to Northwestern University. • The second set of bone samples will be received at the UK BDRL and will be processed for undecalcified sectioning and evaluation of bone. Upon receipt of specimens at UK, an identification code is assigned to the patient and a record is started in the databank. Identifiers will be included on the specimen labeling and in the databank for reduction of error following the CAP protocol, but only accessible by center-approved personnel. No patient identifiers will be given to outside researchers. The samples will be processed for analysis under brightfield light microscopy, polarized light microscopy, and florescent light microscopy.
StatusActive
Effective start/end date9/16/225/31/24

Funding

  • Columbia University: $67,669.00

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