Increased Heparanase Levels in Urine during Acute Puumala Orthohantavirus Infection Are Associated with Disease Severity

Abstract

Old–world orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS), characterized by acute kidney injury (AKI) with transient proteinuria. It seems plausible that proteinuria during acute HFRS is mediated by the disruption of the glomerular filtration barrier (GFB) due to vascular leakage, a hallmark of orthohantavirus–caused diseases. However, direct infection of endothelial cells by orthohantaviruses does not result in increased endothelial permeability, and alternative explanations for vascular leakage and diminished GFB function are necessary. Vascular integrity is partly dependent on an intact endothelial glycocalyx, which is susceptible to cleavage by heparanase (HPSE). To understand the role of glycocalyx degradation in HFRS–associated proteinuria, we investigated the levels of HPSE in urine and plasma during acute, convalescent and recovery stages of HFRS caused by Puumala orthohantavirus. HPSE levels in urine during acute HFRS were significantly increased and strongly associated with the severity of AKI and other markers of disease severity. Furthermore, increased expression of HPSE was detected in vitro in orthohantavirus–infected podocytes, which line the outer surfaces of glomerular capillaries. Taken together, these findings suggest the local activation of HPSE in the kidneys of orthohantavirus–infected patients with the potential to disrupt the endothelial glycocalyx, leading to increased protein leakage through the GFB, resulting in high amounts of proteinuria.

High levels of exfoliated fragments following glycocalyx destruction in hemorrhagic fever with the renal syndrome are associated with mortality risk

“…In addition, HS and CS were significantly associated with the death of HFRS in the Kaplan–Meier survival analysis, both of which also demonstrated obvious predictive efficiency for the prognosis (death) of HFRS by the ROC analysis. Interestingly, the expression of heparanase in the urine, plasma, and podocytes of glomerular capillaries was also increased in PUUV-infected patients and was strongly associated with the markers of severity (such as AKI and proteinuria) in HFRS patients ( 37 ). Both of these findings also indicated that there may be destruction and shedding of the glycocalyx in HFRS patients.…”

Innate lymphoid cells are activated and their levels correlate with viral load in patients with Puumala hantavirus caused hemorrhagic fever with renal syndrome

“…The severity of the patients was assessed with a scoring system based on platelet counts, creatinine values, and mean arterial blood pressure values, as previously describe. 61,62 Two patients scored as severe, while all other scored as mild ( Suppl Table 2 ).…”

“…Patients were stratified as having either mild or severe HFRS based on a scoring system adapted from the sequential organ failure assessment mild. 61,62 As controls, PBMCs were obtained from buffy coats from 10 healthy blood donors from the Blood Transfusion Clinic at the Karolinska University Hospital Huddinge, Stockholm, Sweden (ethical permit nr. 2020-02604) and stored in liquid nitrogen until further use.…”

Nanodrugs alleviate acute kidney injury: Manipulate RONS at kidney

“…The glomerular filtration system bears the brunt of the damage when the kidney experiences ischemia or is exposed to harmful substances [ 40 ]. For instance, podocyte damage, glycocalyx loss and even apoptotic cell death are observed in AKI [ [41] , [42] , [43] , [44] , [45] ] ( Fig.3 B, ii). Renal tubular filtration system lesions allow harmful substances to more easily cross the barrier and accumulate in the renal tubules ( Fig.…”