ALTERATIONS IN HISTIDINE METABOLISM IS A FEATURE OF EARLY AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

• Published in: Transactions of the American Clinical and Climatological Association 2024, Vol.134, p.47-65
• Main Authors: Chapman, Arlene, Chen, Peili
• Format: Article
• Language: English
• Subjects: Adult; Biomarkers - blood; Biomarkers - urine; Case-Control Studies; Cells, Cultured; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Glomerular Filtration Rate; Histidine - metabolism; Humans; Kidney - metabolism; Kidney - pathology; Male; Metabolomics; Middle Aged; Polycystic Kidney, Autosomal Dominant - metabolism; Polycystic Kidney, Autosomal Dominant - pathology; Polycystic Kidney, Autosomal Dominant - physiopathology
• ISSN: 0065-7778

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by epithelial proliferation and progressive cyst enlargement. Using a non-targeted high-resolution metabolomics approach, we analyzed biofluids from 36 ADPKD and 18 healthy controls with estimated glomerular filtration rate (eGFR) > 60 ml/min to identify features specific to ADPKD or that associate with disease severity [eGFR or height-corrected total kidney volume (htTKV)]. Multiple pathways differed between ADPKD subjects and controls, with the histidine pathway being the most highly represented. Plasma histidine, urinary N-methylhistamine, methylimidazole-acetaldehyde, and imidazole-acetaldehyde, as well as 3-methylhistidine and anserine were increased, while plasma N-acetylhistamine and urinary imidazole-acetic acid were decreased in ADPKD compared to controls. In ADPKD, urinary histidine and a histidine derivative, urocanate (a precursor of glutamate), were significantly associated. HtTKV and eGFR were inversely associated with urinary glutamine and plasma 4-imidazolone-5-propionic acid, respectively. Supernatant from cultured human ADPKD renal cystic epithelia demonstrated increased aspartate and glutamate levels at 8 and 24 hours compared to primary tubular epithelia (p < 0.001). Following exposure over 48 hours to α-fluromethylhistidine, an inhibitor of histamine production, primary human cyst epithelia proliferation increased significantly from baseline (p < 0.01) and greater than non-cystic epithelia (p < 0.05). The histidine ammonia lyase inhibitor nitromethane reversed α-fluromethylhistidine-induced cyst epithelia proliferation indicating a role for glutamate in cyst growth. In conclusion, histidine metabolism is altered preferentially leading to glutamate production and epithelial proliferation in ADPKD and associates with disease severity.