Urinary sediment GATA-3 mRNA levels are elevated and T-bet mRNA levels are decreased during acute illness in PUUV-induced severe AKI.

<p>Severe AKI is >3-fold rise in serum Cr during acute illness compared to a 6 month baseline. Illness day 1 is the first calendar day of reported fever. a) Urinary sediment CD3ε mRNA relative expression compared to 2 week baseline value b) Urinary sediment GATA-3 mRNA relative expression compared to 2 week baseline value c) Urinary sediment T-bet mRNA relative expression compared to 2 week baseline value. Symbols and error bars are mean±S.E.</p

Maximum urine IL-6, plasma IL-6, and urine IL-8 concentrations are positively correlated with the degree of PUUV-induced AKI.

<p>a) maximum urine IL-6 levels b) maximum plasma IL-6 levels c) maximum urine IL-8 levels d) maximum plasma IL-8 levels.</p

Characteristics of study subjects with PUUV nephropathia epidemica.

a<p>AKI = acute kidney injury; severe AKI = >3-fold rise in serum creatinine during acute illness compared to a 6 month baseline value.</p>b<p>Values are median (95% confidence interval of median).</p

Clinical laboratory indicators in study subjects with PUUV nephropathia epidemica.

a<p>AKI = acute kidney injury; severe AKI = >3-fold rise in serum creatinine during acute illness compared to a 6 month baseline value.</p>b<p>Values are median (95% confidence interval of median).</p

Multivariate statistical models for acute kidney injury in study subjects with PUUV nephropathia epidemica.

a<p>Odds ratio (OR) for developing severe PUUV-induced acute kidney injury (AKI) compared to non-severe AKI. Severe AKI = >3-fold rise in serum creatinine during acute illness compared to a 6 month baseline value.</p>b<p>95% confidence interval (CI) for the Odds Ratio.</p>c<p>log₁₀ transformed variable.</p>d<p>White blood cell (WBC).</p>e<p>Linear regression of log₁₀ transformed peak creatinine ratio vs. log₁₀ transformed variables.</p>f<p>95% confidence interval (CI) for the linear regression coefficient.</p

Endothelial Nitric Oxide Synthase G894T Polymorphism Associates with Disease Severity in Puumala Hantavirus Infection

<div><p>Introduction</p><p>Hantavirus infections are characterized by both activation and dysfunction of the endothelial cells. The underlying mechanisms of the disease pathogenesis are not fully understood. Here we tested the hypothesis whether the polymorphisms of endothelial nitric oxide synthase, eNOS G894T, and inducible nitric oxide synthase, iNOS G2087A, are associated with the severity of acute Puumala hantavirus (PUUV) infection.</p><p>Patients and Methods</p><p>Hospitalized patients (n = 172) with serologically verified PUUV infection were examined. Clinical and laboratory variables reflecting disease severity were determined. The polymorphisms of eNOS G894T (Glu298Asp, rs1799983) and iNOS G2087A (Ser608Leu, rs2297518) were genotyped.</p><p>Results</p><p>The rare eNOS G894T genotype was associated with the severity of acute kidney injury (AKI). The non-carriers of G-allele (TT-homozygotes) had higher maximum level of serum creatinine than the carriers of G-allele (GT-heterozygotes and GG-homozygotes; median 326, range 102–1041 vs. median 175, range 51–1499 μmol/l; p = 0.018, respectively). The length of hospital stay was longer in the non-carriers of G-allele than in G-allele carriers (median 8, range 3–14 vs. median 6, range 2–15 days; p = 0.032). The rare A-allele carriers (<i>i</i>.<i>e</i>. AA-homozygotes and GA-heterozygotes) of iNOS G2087A had lower minimum systolic and diastolic blood pressure than the non-carriers of A-allele (median 110, range 74–170 vs.116, range 86–162 mmHg, p = 0.019, and median 68, range 40–90 vs. 72, range 48–100 mmHg; p = 0.003, respectively).</p><p>Conclusions</p><p>Patients with the TT-homozygous genotype of eNOS G894T had more severe PUUV-induced AKI than the other genotypes. The eNOS G894T polymorphism may play role in the endothelial dysfunction observed during acute PUUV infection.</p></div

Line chart showing soluble urokinase-type plasminogen activator receptor (suPAR) maximum (median 8.7 ng/ml, range 4.0–18.2 ng/ml) and convalesce phase concentrations (median 4.7 ng/ml, range 2.4–12.2 ng/ml) in relation to the onset of fever (day 0) in 97 patients with Puumala hantavirus infection (P-value for the difference <0.001).

<p>Short title: Line chart showing suPAR maximum and convalescence concentrations in relation to the onset of fever.</p

The clinical and laboratory findings in 172 patients with acute Puumala hantavirus infection.

<p>Abbreviation: CRP, C-reactive protein.</p><p>Normal values: CRP < 10 mg/ml, creatinine ≤ 100 μmol/l for males and ≤ 90 μmol/l for females, platelet count 150–360 x 10⁹/l, leukocyte count 3.4–8.2 x 10⁹/l, hematocrit 0.35–0.50 for males and 0.35–0.46 for females.</p><p>*Equals to the onset of illness before the first blood test was taken.</p><p>**Change in weight during hospital stay reflects the fluid accumulation in the body during the oliguric phase.</p><p>The clinical and laboratory findings in 172 patients with acute Puumala hantavirus infection.</p

The genotype distributions and allele frequencies in 167 patients for eNOS G894T (rs1799983) and in 166 patients for iNOS G2087A (rs2297518) out of 172 patients with acute Puumala hantavirus infection^*.

<p>Abbreviations: eNOS = endothelial nitride oxide synthase, iNOS = inducible nitride oxide synthase.</p><p>*The genotyping was successful in 167 patients for eNOS and in 166 patients for iNOS.</p><p>The genotype distributions and allele frequencies in 167 patients for eNOS G894T (rs1799983) and in 166 patients for iNOS G2087A (rs2297518) out of 172 patients with acute Puumala hantavirus infection<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142872#t002fn002" target="_blank">^*</a>.</p

Box plots of the maximum plasma creatinine (A), hematocrit (B) and leukocyte count in TT-homozygotes (n = 10) and GT-heterozygotes or GG-homozygotes (n = 157) of eNOS G894T(rs1799983) polymorphism in 169 patients with PUUV infection.

<p>Box plot illustrates median (thick line inside box), 25^th and 75^th percentiles (box), and range (whiskers). Extremes and outliers have been omitted from the figure.</p