Association of Plasminuria with Overhydration in Patients with CKD

Abstract

Background and objectives Hypervolemia is a common feature of patients with CKD and associated with hypertension. Recent work has shown stimulation of sodium retention by urinary plasmin during nephrotic syndrome. However, it is unclear whether plasminuria plays a role in patients with stable CKD and non-nephrotic proteinuria.Design, setting, participants, & measurements In this cross-sectional study, we analyzed the fluid status of 171 patients with CKD consecutively presenting to our outpatient clinic from 2012 to 2013 using bioimpedance spectroscopy (Body Composition Monitor [BCM]; Fresenius Medical Care, Germany) and its associations to the urinary excretion of plasminogen and plasmin from a spot urine sample. Two-electrode voltage clamp measurements were performed in Xenopus laevis oocytes expressing human epithelial sodium channel to investigate whether plasmin in concentrations found in urine can activate the channel.Results Overhydration .5% and overhydration .10% of the extracellular volume were found in 29% and 17% of the patients, respectively, and overhydration was associated with edema, hypertension, higher stages of CKD, and proteinuria. Proteinuria was the strongest independent predictor for overhydration (+0.58 L/1.73 m 2 per 10-fold increase; P,0.001). Urinary excretion of plasmin(ogen) quantified by ELISA correlated strongly with proteinuria (r=0.87) and overhydration (r=0.47). Using a chromogenic substrate, active plasmin was found in 44% of patients and correlated with proteinuria and overhydration. Estimated urinary plasmin concentrations were in a range sufficient to activate epithelial sodium channel currents in vitro. In multivariable analysis, urinary excretion of plasmin(ogen) was associated with overhydration similar to proteinuria.Conclusions Hypervolemia in patients with CKD is strongly associated with proteinuria, even in the nonnephrotic range. Protein-rich urine contains high amounts of plasminogen and active plasmin, rendering plasminuria as a possible link between proteinuria and hypervolemia.

Rebuttal to editorial: Sodium retention by uPA in nephrotic syndrome?

“…We agree with Prof. Ehmke that in nephrotic mice with genetic uPA deletion the formation of plasmin from plasminogen may not be completely suppressed. We also agree that very low concentrations of plasmin are sufficient to cause proteolytic ENaC activation as we have previously shown in vitro . Therefore, we cannot rule out the possibility that in nephrotic uPA knockout mice very low concentrations of urinary plasmin may contribute to proteolytic ENaC activation.…”

“…We also agree that very low concentrations of plasmin are sufficient to cause proteolytic ENaC activation as we have previously shown in vitro. 5 Therefore, we cannot rule out the possibility that in nephrotic uPA knockout mice very low concentrations of urinary plasmin may contribute to proteolytic ENaC activation. Importantly, this does not challenge our main conclusion that uPA is not essential for sodium retention in nephrotic syndrome.…”

Diuretic Resistance

“…31–34 Of interest, a recent study analyzed whether this mechanism could also play a role in patients with CKD who did not have nephrotic-range proteinuria. 35 To this end, the authors performed a cross-sectional study in 171 outpatients with CKD (different cause and stages and varying degrees of proteinuria) and 2 control groups including healthy volunteers and patients with nephrotic syndrome. The investigators found that proteinuria was the strongest independent predictor for hypervolemia, as assessed by bioimpedance spectroscopy.…”

Amiloride resolves resistant edema and hypertension in a patient with nephrotic syndrome; a case report

“…Proteinuria is associated with urinary serine protease activity primarily due to aberrant filtration of these proteases across a damaged glomerular filtration barrier (Schork et al. ; Svenningsen et al. , ).…”

“…ENaC has a key role in regulation of the extracellular fluid volume and blood pressure, but besides activation by regulatory hormones, specific proteases can activate the channel (Kleyman et al 2009;Orce et al 1980;Passero et al 2008;Vallet et al 1997). Proteinuria is associated with urinary serine protease activity primarily due to aberrant filtration of these proteases across a damaged glomerular filtration barrier (Schork et al 2016;Svenningsen et al 2009Svenningsen et al , 2012. Volume retention in NS was prevented by a protease inhibitor (Bohnert et al 2017).…”