The Degree of Leukocytosis and Urine GATA-3 mRNA Levels Are Risk Factors for Severe Acute Kidney Injury in Puumala Virus Nephropathia Epidemica

Daniel H Libraty,Mikko Hurme,Antti Vaheri,Jennifer Vlk,Francis A Ennis,Jukka Mustonen,Satu Mäkelä

doi:10.1371/journal.pone.0035402

Daniel H Libraty, Mikko Hurme + Show 5 more

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https://doi.org/10.1371/journal.pone.0035402

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Abstract

Puumala hantavirus (PUUV) infection, also known as nephropathia epidemica, is the most common cause of hemorrhagic fever with renal syndrome (HFRS) in Europe. The pathogenesis of PUUV nephropathia epidemica is complex and multifactorial, and the risk factors for severe acute kidney injury (AKI) during acute PUUV infection are not well defined. We conducted a prospective study of hospitalized patients with PUUV infection in Tampere, Finland to identify acute illness risk factors for HFRS severity. Serial daily blood and urine samples were collected throughout acute illness and at 2 week and 6 month convalescent visits. By univariate analyses, the maximum white blood cell count during acute illness was a risk factor for severe AKI. There were no significant associations between PUUV-induced AKI severity and platelet counts, C-reactive protein, or alanine aminotransferase levels. Maximum plasma interleukin (IL)-6, urine IL-6, and urine IL-8 concentrations were positively associated with PUUV-induced AKI. Finally, the maximum urinary sediment GATA-3 mRNA level was positively correlated with the peak fold-change in serum creatinine, regardless of AKI severity classification. By multivariate analyses, we found that the maximum levels of leukocytes and urinary sediment GATA-3 mRNA during acute illness were independent risk factors for severe PUUV-induced AKI. We have identified novel acute illness risk factors for severe PUUV-induced AKI.

Highlights

Puumala hantavirus (PUUV) infection, known as nephropathia epidemica (NE), is the most common cause of hemorrhagic fever with renal syndrome (HFRS) in Europe [1]
Serial daily blood and urine samples were collected in all study subjects throughout their hospital course, and at convalescent visits 2 weeks and 6 months after hospitalization. 15 patients (42%) developed severe acute kidney injury (AKI); two patients required hemodialysis support, and all patients recovered from their PUUV infection without serious sequelae
There were no significant differences in the baseline characteristics and days of fever at clinical presentation between the patients with severe AKI and those with non-severe AKI (Table 1)

Summary

Introduction

Puumala hantavirus (PUUV) infection, known as nephropathia epidemica (NE), is the most common cause of hemorrhagic fever with renal syndrome (HFRS) in Europe [1]. Human leukocyte alloantigen (HLA) B8 and DRB1*0301 alleles are associated with severe clinical disease, and genetic polymorphisms of the cytokines tumor necrosis factor alpha, interleukin-1 (IL-1), and interleukin-1 receptor antagonist (IL-1Ra) influence the outcome of infection [3,4]. The surface density of platelet b3 integrin, the cellular receptor of hantaviruses, is associated with disease severity in patients infected with Hantaan virus [5], another HFRS inducing hantavirus. Two reports have found that serum and urine levels of interleukin-6 (IL-6) correlated with PUUV HFRS severity [6,7]. We conducted a prospective study of hospitalized patients with PUUV infection in Tampere, Finland to identify acute illness risk factors for HFRS severity. We found that the maximum levels of leukocytes and urinary sediment GATA-3 mRNA [9] during acute illness were independent risk factors for severe PUUV-induced AKI

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