Urinary Plasminogen as a Marker of Disease Progression in Human Glomerular Disease.

RATIONALE & OBJECTIVE: Glomerular disorders have a highly variable clinical course and biomarkers that reflect molecular mechanisms underlying progression are needed. Based on our previous work identifying plasminogen as a direct cause of podocyte injury, we designed this study to test the association between urine plasmin(ogen) (i.e., plasmin and its precursor plasminogen) and end-stage kidney disease (ESKD).

STUDY DESIGN: Multicenter cohort study.

SETTING & PARTICIPANTS: 1010 patients enrolled in the CureGN Cohort with biopsy-proven glomerular disease (focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A nephropathy).

PREDICTORS: The main predictor was urine plasmin(ogen) at baseline. Levels were measured by an electro-chemiluminescent immunoassay developed de novo. Traditional clinical and analytical characteristics were used for adjustment. The ratio of urine plasmin(ogen)/ expected plasmin(ogen) was evaluated as a predictor in a separate model.

OUTCOMES: Progression to ESKD.

ANALYTICAL APPROACH: Cox regression was used to examine the association between urinary plasmin(ogen) and time to ESKD. Urinary markers were Log2 transformed to approximate normal distribution and normalized to urine creatinine (Log2uPlasminogen/Cr, Log2 urinary protein/Cr [UPCR]). Expected plasmin(ogen) was calculated by multiple linear regression.

RESULTS: Adjusted Log2uPlasminogen/Cr was significantly associated with ESKD (HR per doubling Log2uPlasminogen/Cr 1.31 (95% confidence interval [CI] 1.22-1.40), P < 0.001). Comparison of the predictive performance of the models including Log2uPlasminogen/Cr, Log2UPCR or both markers showed the plasmin(ogen) model superiority. The ratio of measured/expected urine plasmin(ogen) was independently associated with ESKD, HR 0.41 (95% CI 0.22-0.77) if ratio < 0.8 and HR 2.42 (95% CI 1.54-3.78) if ratio > 1.1 (compared to ratio between 0.8-1.1).

LIMITATIONS: Single plasmin(ogen) determination does not allow for the study of changes over time. The use of a cohort of mostly white patients and the restriction to patients with 3 glomerular disorders limits the external validity of our analysis.

CONCLUSIONS: Urinary plasmin(ogen) and the ratio of measured/expected plasmin(ogen) are independently associated with ESKD in a cohort of patients with glomerular disease. Taken together with our previous experimental findings, urinary plasmin(ogen) could be a useful biomarker in prognostic decision making and a target for the development of novel therapies in patients with proteinuria and glomerular disease.