Kynurenines in polycystic kidney disease
Jost Klawitter1, Matthew J Jackson1, Peter H Smith1
1Department of Anesthesiology, University of Colorado School of Medicine, University of Colorado Denver Anschutz Medical Campus, 12705 E Montview Blvd, Bioscience 2, Suite 200, Aurora, CO, 80045-7109, USA.
Insights
Tryptophan metabolism is altered in Autosomal dominant polycystic kidney disease (ADPKD), with elevated kynurenines linked to disease severity. Targeting kynurenine production may offer a new therapeutic approach for ADPKD.
Area of Science:
- Nephrology
- Metabolic pathways
- Inflammation research
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by kidney cyst development and interstitial inflammation.
- Tryptophan metabolism and its byproducts, kynurenines, are implicated in inflammatory and oxidative stress pathways, suggesting a potential role in ADPKD pathogenesis.
Purpose of the Study:
- To investigate the association of kynurenines with disease severity and progression in pediatric and adult ADPKD patients.
- To compare kynurenine levels in ADPKD patients with age-matched healthy controls.
Main Methods:
- Collected data from a longitudinal cohort of ADPKD patients and healthy controls.
- Measured key tryptophan metabolites in plasma using liquid chromatography-mass spectrometry.
- Assessed associations between kynurenines, height-corrected total kidney volume (HtTKV), and estimated glomerular filtration rate (eGFR).
Main Results:
- Significant accumulation of kynurenine and kynurenic acid (KYNA) observed in ADPKD patients compared to controls.
- Downstream kynurenines and inflammatory markers (IL-6, MCP-1) increased in adult ADPKD patients.
- KYNA and kynurenine/tryptophan ratio positively correlated with ADPKD severity (HtTKV and eGFR).
Conclusions:
- Kynurenine metabolism is dysregulated in ADPKD.
- Inhibiting kynurenine production may represent a novel therapeutic strategy to slow ADPKD progression.
Background:
Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder, characterized by kidney cyst formation. A major pathological feature of ADPKD is the development of interstitial inflammation. Due to its role in inflammation and oxidative stress, tryptophan metabolism and related kynurenines may have relevance in ADPKD.
Methods:
Data were collected from a well-characterized longitudinal cohort of pediatric and adult patients with ADPKD and compared to age-matched healthy subjects. To evaluate the role of kynurenines in ADPKD severity and progression, we investigated their association with height-corrected total kidney volume (HtTKV) and kidney function (estimated glomerular filtration rate (eGFR)). Key tryptophan metabolites were measured in plasma using a validated liquid chromatography-mass spectrometry assay.
Results:
There was a significant accumulation of kynurenine and kynurenic acid (KYNA) in children and adults with ADPKD as compared to healthy subjects. Downstream kynurenines continued to accumulate in adults with ADPKD concurrent with the increase of inflammatory markers IL-6 and MCP-1. Both markers remained unchanged in ADPKD as compared to healthy children, suggesting alternate pathways responsible for the observed rise in kynurenine and KYNA. KYNA and kynurenine/tryptophan positively associated with disease severity (HtTKV or eGFR) in patients with ADPKD. After Bonferroni adjustment, baseline kynurenines did not associate with disease progression (yearly %change in HtTKV or yearly change in eGFR) in this limited number of patients with ADPKD.
Conclusion:
Kynurenine metabolism seems dysregulated in ADPKD as compared to healthy subjects. Inhibition of kynurenine production by inhibition of main pathway enzymes could present a novel way to reduce the progression of ADPKD.
More Related Videos
07:04A High-performance Liquid Chromatography Measurement of Kynurenine and Kynurenic Acid: Relating Biochemistry to Cognition and Sleep in Rats
Published on: August 19, 2018
08:46Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium
Published on: September 1, 2015
Related Concept Videos
01:10Nephrons
01:28Chronic Kidney Disease III: Interprofessional Care
01:24Chronic Kidney Disease II: Clinical Manifestations
01:20Renal Corpuscle
Glomerulus: Structure and Function
The glomerulus is a tiny, intricate network of capillaries located at the beginning of the nephron. It's enveloped by the Bowman's capsule and receives its blood supply from an afferent arteriole, which divides into numerous...
01:24Nephrotic Syndrome I : Introduction
01:28Renal Drug Excretion: Tubular Secretion