Urine peptidome analysis predicts risk of end-stage renal disease and reveals proteolytic pathways involved in autosomal dominant polycystic kidney disease progression.
Background
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by slowly progressive bilateral renal cyst growth ultimately resulting in loss of kidney function and end-stage renal disease (ESRD). Disease progression rate and age at ESRD are highly variable. Therapeutic interventions therefore require early risk stratification of patients and monitoring of disease progression in response to treatment.


Methods
We used a urine peptidomic approach based on capillary electrophoresis-mass-spectrometry (CE-MS) to identify potential biomarkers reflecting the risk for early progression to ESRD in the Consortium of Radiologic Imaging in Polycystic Kidney Disease (CRISP) cohort.


Results
A biomarker-based classifier consisting of 20 urinary peptides allowed the prediction of ESRD within 10-13 years of follow-up in patients 24-46 years of age at baseline. The performance of the biomarker score approached that of height-adjusted total kidney volume (htTKV) and the combination of the biomarker panel with htTKV improved prediction over either one alone. In young patients (<24 years at baseline), the same biomarker model predicted a 30 mL/min/1.73 m 2 glomerular filtration rate decline over 8 years. Sequence analysis of the altered urinary peptides and the prediction of the involved proteases by in silico analysis revealed alterations in distinct proteolytic pathways, in particular matrix metalloproteinases and cathepsins.


Conclusion
We developed a urinary test that accurately predicts relevant clinical outcomes in ADPKD patients and suggests altered proteolytic pathways involved in disease progression.
['Pejchinovski|Martin|M|', 'Siwy|Justyna|J|', 'Metzger|Jochen|J|', 'Dakna|Mohammed|M|', 'Mischak|Harald|H|', 'Klein|Julie|J|', 'Jankowski|Vera|V|', 'Bae|Kyongtae T|KT|', 'Chapman|Arlene B|AB|', 'Kistler|Andreas D|AD|']
D000293:Adolescent D000328:Adult D015415:Biomarkers D018450:Disease Progression D019075:Electrophoresis, Capillary D005260:Female D005500:Follow-Up Studies D005919:Glomerular Filtration Rate D006801:Humans D007676:Kidney Failure, Chronic D008297:Male D013058:Mass Spectrometry D008875:Middle Aged D010455:Peptides D016891:Polycystic Kidney, Autosomal Dominant D012306:Risk D016482:Urinalysis D055815:Young Adult
progression ADPKD ESRD urinary peptides proteases prediction