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Estimation of Urinary Nanocrystals in Humans using Calcium Fluorophore Labeling and Nanoparticle Tracking Analysis
Published on: February 9, 2021
Oral Covalent Organic Frameworks as Dysbiosis-Mitigating Oxalate Sequestrants for Crystalline Nephropathy
Tianzhi Liu1, Xiaolin Cui1, Jiangzhi Chen2
1School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, P. R. China.
Abstract:
Hyperoxaluria-related crystalline nephropathy progresses through a dynamic interplay among oxalate crystallization, renal inflammatory cascades, and gut dysbiosis. However, concurrent interventions for these interconnected pathways remain elusive. Here, we leverage the gut-kidney axis to address this multifaceted renal issue by employing cationic covalent organic frameworks (COFs) as dysbiosis-mitigating oxalate sequestrants. Oxalate adsorption assays and density functional theory calculations identify the HCl-activated pyridine-functionalized COF1-Cl with superior oxalate adsorption capacity (94.5 mg g-1) and selectivity. Oral administration of COF1-Cl in a rat model of hyperoxaluria effectively sequestrates oxalate within the gut and facilitates the transcellular secretion of serum oxalate into the intestinal lumen by upregulating the oxalate transporter (SLC26A6), resulting in decreased urinary oxalate excretion. Oxalate sequestration by COF1-Cl restores the gut microbiota diversity and promotes the rebalance of typical bacteria associated with oxalate metabolism, stone formation risk, and immune homeostasis. This local gut effect inhibits renal oxalate crystal deposition and NLRP3 inflammasome activation, resulting in amelioration of renal function as evidenced by improved glomerular filtration and decreased blood creatinine and urea nitrogen levels. COF1-Cl also demonstrates good biosafety due to its inert and nonabsorbable nature. This work highlights the potential of utilizing a gut-restricted porous crystalline framework to address metabolism-driven pathology via gut-organ crosstalk.
Insights
Covalent organic frameworks (COFs) can reduce kidney damage from hyperoxaluria by capturing oxalate in the gut. This novel approach restores gut health and improves kidney function, offering a promising new treatment strategy.
Area of Science:
- Materials Science
- Nephrology
- Microbiology
Background:
- Hyperoxaluria causes kidney damage through oxalate crystallization, inflammation, and gut dysbiosis.
- Current treatments lack concurrent intervention for these interconnected pathways.
- Targeting the gut-kidney axis offers a novel therapeutic strategy.
Purpose of the Study:
- To develop and evaluate cationic covalent organic frameworks (COFs) as oxalate sequestrants for hyperoxaluria.
- To investigate the efficacy of COF1-Cl in mitigating gut dysbiosis and renal pathology.
- To explore the gut-kidney crosstalk mechanisms influenced by COF1-Cl.
Main Methods:
- Oxalate adsorption assays and density functional theory (DFT) calculations to screen COFs.
- In vivo studies using a rat model of hyperoxaluria.
- Analysis of gut microbiota diversity, oxalate transporter expression (SLC26A6), renal crystal deposition, and kidney function markers (creatinine, blood urea nitrogen).
Main Results:
- HCl-activated pyridine-functionalized COF1-Cl exhibited high oxalate adsorption capacity (94.5 mg g⁻¹) and selectivity.
- Oral COF1-Cl administration reduced serum and urinary oxalate levels in rats.
- COF1-Cl restored gut microbiota diversity, inhibited renal oxalate deposition, and improved kidney function.
- COF1-Cl demonstrated good biosafety, being inert and nonabsorbable.
Conclusions:
- Cationic COFs can effectively sequester oxalate in the gut, addressing hyperoxaluria-related kidney disease.
- COF1-Cl modulates the gut-kidney axis by improving gut dysbiosis and enhancing oxalate transport.
- This gut-restricted porous material presents a promising therapeutic approach for metabolism-driven kidney pathologies.
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