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BackgroundNephropathia epidemica (NE) is a Scandinavian type of hemorrhagic fever with renal syndrome caused by Puumala hantavirus. The clinical course of the disease varies greatly in severity. The aim of the present study was to evaluate whether plasma C-reactive protein (CRP) and interleukin (IL)-6 levels associate with the severity of NE.MethodsA prospectively collected cohort of 118 consecutive hospital-treated patients with acute serologically confirmed NE was examined. Plasma IL-6, CRP, and creatinine, as well as blood cell count and daily urinary protein excretion were measured on three consecutive days after admission. Plasma IL-6 and CRP levels higher than the median were considered high.ResultsWe found that high IL-6 associated with most variables reflecting the severity of the disease. When compared to patients with low IL-6, patients with high IL-6 had higher maximum blood leukocyte count (11.9 vs 9.0 × 109/l, P = 0.001) and urinary protein excretion (2.51 vs 1.68 g/day, P = 0.017), as well as a lower minimum blood platelet count (55 vs 80 × 109/l, P < 0.001), hematocrit (0.34 vs 0.38, P = 0.001), and urinary output (1040 vs 2180 ml/day, P < 0.001). They also stayed longer in hospital than patients with low IL-6 (8 vs 6 days, P < 0.001). In contrast, high CRP did not associate with severe disease.ConclusionsHigh plasma IL-6 concentrations associate with a clinically severe acute Puumala hantavirus infection, whereas high plasma CRP as such does not reflect the severity of the disease.

Acute kidney injury (AKI) remains a predominant clinical expression of nephropathia epidemica (NE). Its pathogenesis is not yet fully understood. Here, we describe the tissue injury comprehensively and present new data aimed to characterize the injury and explain its pathophysiology. When compared to tubulointerstitial nephritis of a wide variety of other aetiologies, a high degree of proteinuria is a distinguished trait of NE, a finding that is also helpful in the clinical suspicion of the disease. Recently, novel biomarkers for the prediction of severe AKI, including neutrophil gelatinase-associated lipocalin (NGAL), have been identified and ultrastructural tissue changes have been more accurately described. A role for soluble urokinase-type plasminogen activator (suPAR) in the pathogenesis of NE has been suggested, and data on gene polymorphisms, in relation to the severity of AKI have been presented. Smoking is a risk factor for NE and smoking is also associated with aggravated AKI in NE. Although no specific treatment is in sight, recent case reports concerning therapy directed against vascular permeability and vasodilation are of interest. In fact, future work trying to explain the pathophysiology of AKI might need concentrated efforts towards the mechanisms of increased vascular permeability and vasodilatation, which irrespective of organ manifestation, are two major determinants of NE.

Background:Puumala virus (PUUV)-induced hemorrhagic fever with renal syndrome is common in many European countries. The typical renal histologic lesion is acute tubulointerstitial nephritis. We examined the type and kinetics of urine protein excretion and prognostic significance of proteinuria for the severity of acute kidney injury (AKI) in acute PUUV infection. Methods: The amount of dipstick albuminuria at hospital admission was analyzed in 205 patients with acute PUUV infection. Dipstick albuminuria at admission was graded into 3 categories: 0-1+, 2+, and 3+. In 70 patients, 24-h urinary excretion of protein, overnight urinary excretion of albumin, immunoglobulin (Ig) G, and α1-microglobulin also were measured over 3 consecutive days during the hospital stay. Results: Maximum median daily proteinuria, overnight albuminuria, and IgG excretion were observed over 5 days, while that of creatinine values was observed 9 days after the onset of the disease. The medians of maximum plasma creatinine levels during hospital stay were different in the 3 categories of dipstick albuminuria: 0-1+: 98 µmol/L (58-1,499), 2+: 139 µmol/L (71-829), and 3+: 363 µmol/L (51-1,285; p < 0.001). Dipstick albuminuria ≥2+ at admission could be detected in 89% of the patients who subsequently developed severe AKI. Glomerular proteinuria, but not tubular proteinuria (α1-microglobulin), correlated with the severity of the emerging AKI. Conclusion: In acute PUUV infection, maximum median proteinuria values preceded the most severe phase of AKI by a few days. A highly useful finding for clinical work was that a quick and simple albuminuria dipstick test at hospital admission predicted the severity of the upcoming AKI.

Background: Puumala hantavirus (PUUV) induces an acute tubulointerstitial nephritis and acute kidney injury (AKI). Our aim was to evaluate the prognosis of severe AKI associated with PUUV infection. Methods: We examined 556 patients who were treated at Tampere University Hospital during 1982-2013 for acute, serologically confirmed PUUV infection. Plasma creatinine was measured during hospitalization, convalescence, and 1, 2, and 5 years after the acute infection. Results: Plasma creatinine concentration was elevated (>100 μmol/l) in 459 (83%) patients, while altogether 189 patients (34%) had severe AKI defined as Kidney Disease: Improving Global Outcomes (KDIGO) stage 3, that is, plasma creatinine ≥353.6 μmol/l (4.0 mg/dl) or need of dialysis. There were no fatal cases during the hospitalization or the following 3 months. Fatality rate during the years following PUUV infection did not differ between patients who had suffered from severe AKI versus those without severe AKI. Post-hospitalization plasma creatinine values were available for 188 (34%) patients. One month after the acute infection, patients with prior severe AKI had higher median plasma creatinine concentration (82 µmol/l, range 54-184) than patients without severe AKI (74 µmol/l, range 55-109, p = 0.005). After 1 year, no significant difference existed in median plasma creatinine concentrations between patients with (71 µmol/l, range 36-123) and without prior severe AKI (72 µmol/l, range 34-116, p = 0.711). After 5 years all but 1 patient had normal creatinine levels. Conclusions: In contrast to the worldwide well-accepted KDIGO criteria, severe AKI associated with PUUV infection is not associated with excess fatality but has a very good prognosis, both in the short and long terms.

IntroductionPuumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome called nephropathia epidemica (NE). The aim of the present study was to evaluate plasma cell-free DNA (cf-DNA) levels and urinary cf-DNA excretion in acute NE as well as their associations with the severity of the disease.MethodsTotal plasma cf-DNA was quantified directly in plasma of 61 patients and urine of 20 patients with acute NE. We also carried out a qualitative high-sensitivity lab-on-a-chip DNA assay in 20 patients to elucidate the appearance of cf-DNA in plasma and urine.ResultsThe maximum plasma cf-DNA values taken during acute NE were significantly higher than the control values taken after the hospitalization period (median 1.33 µg/ml, range 0.94–3.29 µg/ml vs. median 0.77 µg/ml, range 0.55–0.99 µg/ml, P<0.001). The maximum plasma cf-DNA levels correlated positively with maximum blood leukocyte count (r = 0.388, P = 0.002) and the length of hospital stay (r = 0.376, P = 0.003), and inversely with minimum blood platelet count (r = −0.297, P = 0.020). Qualitative analysis of plasma cf-DNA revealed that in most of the patients cf-DNA displayed a low-molecular weight appearance, corresponding to the size of apoptotic DNA (150–200 bp). The visually graded maximum cf-DNA band intensity correlated positively with the maximum quantity of total plasma cf-DNA (r = 0.513, P = 0.021). Maximum urinary excretion of cf-DNA in turn was not markedly increased during the acute phase of NE and did not correlate with any of the variables reflecting severity of the disease or with the maximum plasma cf-DNA level.ConclusionsThe plasma levels of cf-DNA are elevated during acute PUUV infection and correlate with the apoptotic cf-DNA-band intensity. The plasma cf-DNA concentration correlates with some variables reflecting the severity of the disease. The urinary excretion of cf-DNA does not reflect the degree of inflammation in the kidney.

Our aim was to investigate whether plasma levels of the long pentraxin-3 (PTX3) associate with the severity of Puumala hantavirus-induced nephropathia epidemica (NE). Sixty-one prospectively identified consecutively hospitalized NE patients were examined. Plasma PTX3, interleukin (IL)-6, terminal complement complex SC5b-9, complement component C3, C-reactive protein (CRP), creatinine, sodium, kynurenine, and tryptophan levels, as well as the blood cell count, were determined for up to five consecutive days after hospitalization. Receiver operating characteristic (ROC) analysis revealed that the maximum PTX3 level >101.6 ng/ml (high PTX3) showed a sensitivity of 71% and a specificity of 89% for detecting platelet level <50 × 10(9)/l, with an area under the curve (AUC) value of 0.78 (95% confidence interval [CI] 0.63-0.94). High PTX3 level was also associated with several other variables reflecting the severity of the disease: patients with high PTX3 level had higher maximum blood leukocyte (16.1 vs. 9.7 × 10(9)/l, p < 0.001), plasma IL-6 (16.9 vs. 9.0 pg/ml, p = 0.007), and creatinine (282 vs. 124 μmol/l, p = 0.007) levels than patients with low maximum PTX3 level. They also had longer hospital stays (8 vs. 5 days, p = 0.015) compared to patients with low PTX3 level. High plasma PTX3 levels are associated with thrombocytopenia and the overall severity of NE.

The severity of thrombocytopenia associates with the degree of inflammation and variables reflecting capillary leakage, but not with the severity of acute kidney injury in PUUV infected Finnish patients.