Urinary Plasmin(ogen) as a Prognostic Factor for Hypertension

Abstract

IntroductionPlasmin and its precursor, plasminogen, are detectable in urine from patients with glomerular disease. Urinary plasmin(ogen) levels correlate with blood pressure (BP) and may contribute to renal Na+ retention by activating the epithelial Na+ channel (ENaC). In a longitudinal nested-cohort study, we asked whether urinary plasmin(ogen) levels predict subsequent increase in BP, incident hypertension, or mortality in subjects with type I diabetes, who often develop proteinuria.MethodsThe Pittsburgh Epidemiology of Diabetes Complications (EDC) study followed up type I diabetic subjects for 25 years. Urine specimens from 70 subjects with a spectrum of baseline urinary albumin levels were examined. Outcomes included increased BP after 2 years (≥1 SD over baseline systolic or diastolic BP, examined via logistic regression), 25-year incident hypertension (≥140/90 mm Hg or initiating BP-lowering medications), and all-cause or cardiovascular mortality, examined using Cox regression.ResultsSubjects experiencing a 2-year increase in BP had higher baseline urinary plasmin(ogen)/creatinine levels (uPl/Cr) than other subjects (P = 0.04); the difference in baseline urinary albumin/creatinine levels (uAlb/Cr) was similar (P = 0.07). Baseline uPl/Cr was associated with increased 25-year hypertension incidence (hazard ratio = 2.05, P = 0.001), all-cause mortality (HR = 2.05, P = 0.01) and cardiovascular mortality (HR = 3.30, P = 0.005), although not independent of uAlb/Cr.ConclusionThis is the first long-term prospective study addressing clinical outcomes associated with increased urinary plasmin(ogen). Findings are consistent with a role for plasmin(ogen) in promoting increased BP, but also demonstrate the difficulty in distinguishing effects due to plasmin(ogen) from those of albuminuria.

Plasminogenuria is associated with podocyte injury, edema, and kidney dysfunction in incident glomerular disease

“…These cross-sectional results are similar to previous findings in the later course of disease, including in patients with stable CKD. 29,39,40 We also observed inverse relationships between the three biomarkers and eGFR at biopsy. This represents the first time-to our knowledge-of a potential relationship between urinary plasmin(ogen) excretion and eGFR in the setting of biopsy-proven glomerular diseases.…”

“…[28][29][30][31][32] The current paradigm for urinary plasminogen has thus primarily focused for the most part on its role in the collecting ducts and its contribution to volume overload status, in large part due to limited studies exploring the potential role of plasmin(ogen)-induced podocyte injury in proteinuric glomerular injury. [38][39][40][41]56,57 It is well established that independent of baseline eGFR or etiology, total proteinuria is a marker of kidney damage and a strong predictor of progression to end-stage renal disease, with increasing proteinuria in the setting of CKD correlating with increased risk of cardiovascular disease and all-cause mortality. [58][59][60][61][62][63] Few reports, however, have identified a role for specific filtered proteins that contribute to kidney damage through cytotoxic effects on podocytes as "second hits."…”

“…Urinary plasmin(ogen) has been previously shown to be associated with hypervolemia in limited patient cohorts. 28,29,[38][39][40][41] To validate these findings across a larger sample size in the setting of biopsy-proven glomerular diseases, we sought to define these relationships within our cohort. At baseline across all subjects, plasmin(ogen)uria (log µg/mg•Cr) was strongly positively correlated with both proteinuria (log mg/mg•Cr; r=0.8348, p<0.0001) and albuminuria (log mg/mg•Cr; r=0.8219, p<0.0001) ( Figure 4).…”

Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility

“…Both types I and II diabetes are associated with higher plasmin(ogen) levels in plasma. A 25-year prospective study of type I diabetes documented an association with increased urinary plasmin(ogen), particularly in hypertensive subjects (69). Concentrations of plasmin(ogen) in urine are correlated with the development of preeclampsia late in preg-JI ET AL.…”

Proteasuria—The impact of active urinary proteases on sodium retention in nephrotic syndrome

“…Up to now, it is not clear if proteinuria is a risk marker that solely reflects kidney damage or if it is involved in the progression of kidney disease by exerting nephrotoxic effects on podocytes and tubuli . In this regard, it could be hypothesized that proteasuria might be involved in kidney damage and progression of kidney failure by direct and also indirect effects . Unlike the evidence of proteasuria influencing sodium handling via ENaC, the role of proteasuria in mediating kidney damage is more speculative and there are only few data supporting this.…”