Urine soluble urokinase‐type plasminogen activator receptor levels correlate with proteinuria in Puumala hantavirus infection

Abstract

Objectives Urokinase-type plasminogen activator receptor (uPAR) is upregulated during inflammation and known to bind to β3-integrins, receptors used by pathogenic hantaviruses to enter endothelial cells. It has been proposed that soluble uPAR (suPAR) is a circulating factor that causes focal segmental glomerulosclerosis and proteinuria by activating β3-integrin in kidney podocytes. Proteinuria is also a characteristic feature of hantavirus infections. The aim of this study was to evaluate the relation between urine suPAR levels and disease severity in acute Puumala hantavirus (PUUV) infection. Design A single-centre, prospective cohort study. Subjects and methods Urinary suPAR levels were measured twice during the acute phase and once during convalescence in 36 patients with serologically confirmed PUUV infection. Fractional excretion of suPAR (FE suPAR) and of albumin (FE alb) were calculated. Results The FE suPAR was significantly elevated during the acute phase of PUUV infection compared to the convalescent phase (median 3.2%, range 0.8–52.0%, vs. median 1.9%, range 1.0–5.8%, P = 0.005). Maximum FE suPAR was correlated markedly with maximum FE alb (r = 0.812, P < 0.001), and with several other variables that reflect disease severity. There was a positive correlation with the length of hospitalization (r = 0.455, P = 0.009) and maximum plasma creatinine level (r = 0.780, P < 0.001), and an inverse correlation with minimum urinary output (r = −0.411, P = 0.030). There was no correlation between FE suPAR and plasma suPAR (r = 0.180, P = 0.324). Conclusion Urinary suPAR is markedly increased during acute PUUV infection and is correlated with proteinuria. High urine suPAR level may reflect local production of suPAR in the kidney during the acute infection.

A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease

“…6) 31–34 . This rationale is supported by the fact that the APOL1 gene encodes a signal peptide sequence that targets newly synthesized protein for secretion, by the fact that exogenously added APOL1 risk-variant proteins, but not the non-risk-variant, affected endocytic machinery within podocytes (formation of autophagosomes)—the mechanism through which APOL1 risk proteins lyse trypanosomes 29 —and lastly, by studies describing suPAR–β 3 integrin-dependent endocytosis of hantaviruses 35,36 . Interestingly, a previous study showed that podocyte-specific expression of APOL1 risk variants in mice resulted in moderate podocyte depletion later in life and occasional preeclampsia 9 .…”

The fundamental role of endothelial cells in hantavirus pathogenesis

“…On the other hand, hantavirus infection of renal glomerular (e.g., podocytes) and tubular cells results in disruption of cell-cell contacts that could directly lead to decreased kidney barrier function and subsequent proteinuria ( Krautkramer et al, 2011 ). Also, soluble urokinase-type plasminogen activator receptor (suPAR), elevated in the plasma and urine of HFRS patients, could affect podocyte integrity ( Outinen et al, 2013 , 2014 ).…”

Community Acquired Severe Acute Kidney Injury Caused by Hantavirus-Induced Hemorrhagic Fever with Renal Syndrome Has a Favorable Outcome

“…The study cohort consisted of 556 PUUV-infected patients, who had participated in our previous clinical studies [12,17,18,19,24,25,26,27,28,29,30,31,32,33,34,37,38,39,40,41]. The diagnosis of acute PUUV infection was serologically confirmed in all cases.…”

“…However, plasma C-reactive protein (CRP) concentration is not associated with the severity of AKI, and it may even be a protective factor for kidney function [25,26,27,28,29,30]. Furthermore, urinary IL-6 and suPAR excretion correlate with proteinuria, which possibly reflects the local production of these molecules in the kidney [31,32]. Nevertheless, the long-term prognosis of acute PUUV infection has been shown to be favorable and is not predicted by the clinical severity of the acute infection [33,34].…”