title: Predicting albuminuria response to spironolactone treatment with urinary proteomics in patients with type 2 diabetes and hypertension.
abstract: The mineralocorticoid receptor antagonist spironolactone significantly reduces albuminuria in patients with diabetes. Prior studies have shown large between-patient variability in albuminuria treatment response. We previously developed and validated a urinary proteomic classifier that predicts onset and progression of chronic kidney disease. Here, we tested whether the proteomic classifier based on 273 urinary peptides (CKD273) predicts albuminuria response to spironolactone treatment.
  
  
  
  We performed a post hoc analysis in a double-blind randomized clinical trial with allocation to either spironolactone 12.5-50 mg/day (n = 57) or placebo (n = 54) for 16 weeks. Patients were diagnosed with type 2 diabetes and resistant hypertension. Treatment was an adjunct to renin-angiotensin system inhibition. Primary endpoint was the percentage change in urine albumin to creatinine ratio (UACR). Capillary electrophoresis mass spectrometry was used to quantify urinary peptides at baseline. The previously validated combination of 273 known urinary peptides was used as proteomic classifier.
  
  
  
  Spironolactone reduced UACR relative to placebo by 50%, although with a large between-patient variability in UACR response (5th to 95th percentile, 7 to 312%). An interaction was detected between CKD273 and treatment assignment (β = -1.09, P = 0.026). Higher values of CKD273 at baseline were associated with a larger reduction in UACR in the spironolactone group (β = -0.70, P = 0.049), but not in the placebo group (β = 0.39, P = 0.25). Stratified in tertiles of baseline CKD273, reduction in UACR was greater in the highest tertile, 63% (95% confidence interval: 35-79%), as compared with the two other tertiles combined, 16% (-17 to 40%) (P = 0.011).
  
  
  
  A urinary proteomics classifier can be used to identify individuals with type 2 diabetes who are more likely to show an albuminuria-lowering response to spironolactone treatment. These results suggest that urinary proteomics may be a valuable tool to tailor therapy, but confirmation in a larger clinical trial is required.
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Lindhardt
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Frederik
authors.initials: F
authors.lastname: Persson
authors.affiliation: University of Southern Denmark, Research Unit for Cardiovascular and renal protection, Odense, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Oxlund
authors.affiliation: University of Southern Denmark, Research Unit for Cardiovascular and renal protection, Odense, Denmark.
authors.forename: Ib A
authors.initials: IA
authors.lastname: Jacobsen
authors.affiliation: Mosaiques Diagnostics, Hannover, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Zürbig
authors.affiliation: Mosaiques Diagnostics, Hannover, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Mischak
authors.affiliation: Faculty of Heath, University of Aarhus, Aarhus, Denmark.|The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Rossing
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hiddo J L
authors.initials: HJL
authors.lastname: Heerspink
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000139:chemically induced / Q000175:diagnosis* / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000009:adverse effects*; D020543:Proteome / Q000032:analysis*; D012084:Renin-Angiotensin System / Q000187:drug effects; D013148:Spironolactone / Q000009:adverse effects*; D016482:Urinalysis; D055815:Young Adult
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D020543:Proteome; D013148:Spironolactone
keywords: diabetes mellitus type II; hypertension; mineralocorticoid receptor antagonists; precision medicine; proteomics