Abstract: SA-PO749
Allopurinol Alters the Metabolome of CKD Patients Beyond Uric Acid-Lowering
Session Information
- CKD: Mechanisms - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Sun, Mingyao, The University of Iowa, Iowa City, Iowa, United States
- Lacina, Nicole Grace, The University of Iowa, Iowa City, Iowa, United States
- Kruse, Nicholas, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
- Buchanan, Jane, The University of Iowa, Iowa City, Iowa, United States
- Zepeda-Orozco, Diana, The University of Iowa, Iowa City, Iowa, United States
- Taylor, Eric, The University of Iowa, Iowa City, Iowa, United States
- Jalal, Diana I., The University of Iowa, Iowa City, Iowa, United States
Background
Allopurinol, a xanthine oxidase (XO) inhibitor, is the most commonly prescribed uric acid-lowering agent in patients with chronic kidney disease (CKD). Although experimental evidence suggests allopurinol has broader effects on the metabolome, these potential effects have not been characterized in CKD. Here, we sought to evaluate the effects of allopurinol on the metabolome of CKD patients.
Methods
Gas chromatography mass spectrometry (GC-MS) was performed on the serum of 31 subjects who participated in a 12-week randomized clinical trial of allopurinol vs placebo. Metabolites of central carbon metabolism included the TCA cycle, glycolysis, the pentose phosphate pathway, amino acid metabolism, neurotransmission, reactive oxygen species defense, and energetics. Metabolites were compared at baseline to the end of study for allopurinol and placebo (paired t test). MetaboAnalyst software was utilized to identify metabolic pathways.
Results
Of the 90 metabolites evaluated by GC-MS, 6 were significantly altered after allopurinol treatment but not placebo (Table). MetaboAnalyst indicated the pentose phosphate (PP) pathway and purine and pyrimidine metabolism were the top pathways affected by allopurinol. Allopurinol inhibited purine metabolism, resulting in decreased serum uric acid (-3.7 ± 1.0mg/dL) vs placebo (0.1 ± 1.5 mg/dL) (p<0.0001) and increased the precursor xanthine. Allopurinol inhibited PP pathway activity as downstream product ribose-5-phosphate decreased and upstream precursor glucose-6-phosphate increased.
Conclusion
We describe, for the first time, important effects of allopurinol on the metabolome of CKD patients. Specifically, PP pathway inhibition is known to contribute to oxidative stress and pyrimidine pathway inhibition is known to increase ammonia. These findings should be confirmed in larger studies and the clinical implications of these broad effects should be explored.
Changes in metabolites by study group
| Metabolite | Pathway | Allopurinol (n=16) | Placebo (n=15) | ||||
| Baseline | End of study | ||||||
| Dihydroxyphenylalanine | Tyrosine metabolism | 1033(267) | 787(310)* | 1069(256) | 1117(312) | ||
| Glucose-6-phosphate | PP pathway | 1214(896) | 1906(1274)# | 1328(897) | 892(510) | ||
| Ribose-5-phosphate | PP pathway, purine metabolism | 1132(265) | 632(187)* | 1147(150) | 1200(200) | ||
| N-acetyltyrosine | Tyrosine metabolism | 1258(312) | 497(183)* | 1279(355) | 1343(400) | ||
| Orotate | Pyrimidine metabolism | 251(82) | 4126(4655)* | 258(128) | 255(184) | ||
| Xanthine | Purine and caffeine metabolism | 466(168) | 3171(2049)* | 511(232) | 506(283) | ||
| Linoleic acid | Lenoleic acid metabollism | 1269(651) | 934(355)* | 1106(427) | 1361(607) | ||
Values are expressed as mean(SD) relative signal intensity *: P value<0.05, #: P value=0.09
Funding
- NIDDK Support