Abstract: FR-PO1080
Tryptophan Metabolite Accumulation in CKD: Unraveling the Link Between Kidney Dysfunction and Brain Injury
Session Information
- CKD Mechanisms: Progression, Fibrosis, and Beyond
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Saliba, Afaf, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Matta, Shane, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Hejazi, Leila, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Debnath, Subrata, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Sharma, Kumar, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
Group or Team Name
- Center for Precision Medicine - Laboratory of Kumar Sharma.
Background
The prevalence of cognitive impairment increases dramatically with the progression of Chronic Kidney Disease (CKD). The underlying pathophysiology of cognitive decline with advanced CKD remains to be established. We performed targeted metabolomics in plasma from patients with CKD stages 3 to 5 and kidney and brain samples from a mouse model of rapid kidney failure.
Methods
Clinical plasma samples were analyzed via mass spectrometry for essential amino acid tryptophan and its metabolites. A mouse kidney failure model was established by MDM2 deletion in proximal tubules in a doxycycline-inducible mouse model. Six days post-doxycycline administration, control and MDM2-conditional knock-out (cKO) mice were sacrificed, and kidneys and brains were harvested for cryosectioning, protein, and RNA extractions. Metabolomics analysis was performed via a Thermo-Orbitrap QExactive HFX) and microfluidic platform (ZipChip, 908 Devices). Data and pathway analysis were performed using MetaboAnalyst 5.0.
Results
Neurotoxic tryptophan metabolite 3-hydroxykynurenine (3-HK) was significantly (p <0.01) elevated in patients with CKD stage 5 (n=8) not-on-dialysis compared to CKD stages 3B and 4 (n=18). Mice lacking MDM2 in the renal tubules (n=4) exhibited aggressive renal tubular loss with increased systemic inflammation based on a significant increase in neutrophils to lymphocytes ratio (p<0.05) and plasma IL-6 levels (p<0.01), compared to control mice (n=4). Metabolomics analysis in plasma samples of MDM2cKO vs. control mice highlighted an accelerated tryptophan degradation via the kynurenine pathway with resultant accumulation of 3-HK levels (p<0.01). 3-HK plasma concentration correlated with plasma creatinine (r=0.82; p<0.01). Interestingly, brain tissue analysis showed increased 3-HK levels (p<0.01). Assessment of the brain cortex of the MDM2cKO mice via TUNEL assay identified a significant increase in apoptotic cells.
Conclusion
Our study indicates that advanced CKD is associated with accelerated tryptophan degradation and increased levels of circulating 3-HK, which can readily cross the blood-brain barrier. Accumulation of 3-HK potentially causes brain cell toxicity and cognitive dysfunction in CKD.
Funding
- Other NIH Support