Abstract: SA-PO411
Metabolic Profiling of Urine from Patients with Cystinuria Provides New Insight into Disease Phenotype, Associated Microbiome Effects, and Treatment Efficacy
Session Information
- Genetic Diseases of the Kidney - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Lewis, Matthew R., Imperial College London, London, United Kingdom
- Chekmeneva, Elena, Imperial College London, London, United Kingdom
- Sands, Caroline, Imperial College London, London, United Kingdom
- David, Mark, Imperial College London, London, United Kingdom
- Whiley, Luke, Imperial College London, London, United Kingdom
- Armstrong, Ada, Imperial College London, London, United Kingdom
- Nazzal, Lama, New York University School of Medicine, New York, New York, United States
- Sahota, Amrik, Rutgers University, Piscataway, New Jersey, United States
- Goldfarb, David S., New York Harbor VAMC, New York, New York, United States
- Takats, Zoltan, Imperial College London, London, United Kingdom
- Asplin, John R., Litholink Corp, Chicago, Illinois, United States
Background
Cystinuria is a disease of impaired absorption of cystine and dibasic amino acids (DAA) from the intestine and renal tubule leading to formation of cystine kidney stones. However, the metabolic impact of reduced amino acid absorption and excessive loss in the urine is poorly understood. We measured endogenous, gut microbial, and xenobiotic metabolites, providing insight into consequences of the disease and its treatment.
Methods
Urinary biochemicals were assayed using LC-MS in 293 urine specimens from patients with cystinuria or control urinary phenotypes. Multivariate statistical analyses were conducted to reveal statistically significant biochemical signatures of the disease and products of cysteine-binding thiol drugs (CBTDs). 16s rRNA gene sequencing was performed on fecal samples from 12 wildtype (WT) and 12 cystinuric (Slc3a1 knockout; KO) mice to evaluate their gut microbial composition.
Results
Cystinuric urine samples had elevated levels of cysteine-γ-glutamyl cystine disulfide (glutathione precursor), indole-3-acetic acid (microbial tryptophan metabolism), and novel conjugated forms of putrescine (microbial DAA decomposition). Conversely, taurine (sulfur metabolism), indole-3-acetic acid-glucuronide, and novel urinary metabolite N-methyl pipecolic acid (lysine metabolism) were reduced in cystinuric urine. Where cysteine-bound CBTDs were observed, substantial amounts of “wasted” drug were also detected as CBTD homodimers, non-cysteine disulfides, and mixed drug disulfides. The differentiation of gut microbially-derived metabolites led us to evaluate the gut microbiome diversity and composition in a mouse model of cystinuria revealing clear beta diversity and taxa differentiation between WT and KO mice.
Conclusion
Cystinuria is associated with unique urinary metabolic profiles beyond hyperexcretion of cystine and DAA, indicating perturbed metabolic processes and potential gut microbial effects. Study of the gut microbiome of WT and KO mice provides the first evidence for them having distinct taxa, perhaps due to poorly absorbed DAA present in the intestinal lumen. Urinary profiles allow us to characterize the excretion profiles of CBTDs, providing insight which may be helpful to tailor treatment.
Funding
- Government Support - Non-U.S.