Annually, over 10,000 cases of hemorrhagic fever with renal syndrome (HFRS) are diagnosed in Europe. Puumala hantavirus (PUUV) causes most of the European HFRS cases. PUUV causes usually a relatively mild disease, which is rarely fatal. However, the severity of the infection varies greatly, and factors affecting the severity are mostly unrevealed. Host genes are known to have an effect. The typical clinical features in PUUV infection include acute kidney injury, thrombocytopenia, and increased vascular permeability. The primary target of hantavirus is the endothelium of the vessels of different organs. Although PUUV does not cause direct cytopathology of the endothelial cells, remarkable changes in both the barrier function of the endothelium and the function of the infected endothelial cells occur. Host immune or inflammatory mechanisms are probably important in the development of the capillary leakage. Several immunoinflammatory biomarkers have been studied in the context of assessing the severity of HFRS caused by PUUV. Most of them are not used in clinical practice, but the increasing knowledge about the biomarkers has elucidated the pathogenesis of PUUV infection.

• Puumala virus
• biomarker
• hantavirus
• hemorrhagic fever with renal syndrome

Nephrotic syndrome (NS) is relatively common in children, with most of its histological types being minimal changed disease. Its etiology has long been attributed to lymphocyte (especially T-cell) dysfunction, while T-cell-mediated vascular hyperpermeability increases protein permeability in glomerular capillaries, leading to proteinuria and hypoproteinemia. Based on this etiology, steroids and immunosuppressive drugs that are effective against this disease have also been considered to correct T-cell dysfunction. However, in recent years, this has been questioned. The primary cause of NS has been considered damage to glomerular epithelial cells and podocyte-related proteins. Therefore, we first describe the changes in expression of molecules involved in NS etiology, and then describe the mechanism by which abnormal expression of these molecules induces proteinuria. Finally, we consider the mechanism by which infection causes the recurrence of NS.

• Nephrotic syndrome
• Gene
• Immunity
• Viral infection
• Children

• Adult minimal change nephrotic syndrome
• Lymphocytes
• Renal pathology
• Spontaneous remission

Recent reports suggest helper T-cell abnormalities in minimal-change nephrotic syndrome (MCNS), which often complicate allergic disorders that show a similar helper T-cell profile with Th2/Th17 predominance. However, the effect of anti-allergy therapy on MCNS remains unknown. This retrospective study included 51 patients with biopsy-proven MCNS recruited between November 2012 and October 2015, with follow-up through November 2017. We analyzed relapse and temporal daily corticosteroid dose with and without co-administration of histamine H1 receptor antagonist, cetirizine, and cysteinyl-leukotriene receptor antagonist, montelukast, as well as between baseline and after follow-up. Thirteen patients were treated with cetirizine and montelukast in addition to conventional therapy, whereas 38 patients were treated by conventional therapy only, consisting of corticosteroids and immunosuppressants. To adjust for baseline clinical characteristics, a 1:1 propensity score–matched model was applied. The clinical characteristics of the two groups after matching were similar at baseline. The treatment group showed a significant reduction in the lowest daily dose of oral prednisolone throughout the entire treatment course after the study compared to that of baseline (p < 0.025), which was not observed in the control group (p = 0.37), and showed significantly higher percentage of patients establishing corticosteroid-free state for the first time throughout the entire treatment course by addition of cetirizine and montelukast compared to the control group (p < 0.025). The study shows, for the first time, the steroid sparing effect of cetirizine and montelukast in addition to conventional treatment in MCNS patients with concomitant allergies.

DNA methylation plays a crucial role in regulating transcription, and changes in DNA methylation affect gene expression and disease development. Minimal change nephrotic syndrome (MCNS) has been reported to involve immunological disturbances. Since the characteristic features of the disease include recurrent relapse and sex and age preference, the disease pathogenesis may be partly related to epigenetic changes. However, little is known about these changes.

We analyzed genome-wide DNA methylation using the microarray-based integrated analysis of methylation by isoschizomers method. This method was used to evaluate methylation in monocytes (patient number; n = 6) and naïve T helper cells (n = 4) from the peripheral blood of MCNS patients both in relapse and following remission and that of healthy controls (n = 5).

In total, 85 co-occurring genes were identified in naïve T helper cells, while 4 such genes were identified in monocytes, which were common among the 3 following comparisons for changes in DNA methylation using sample pairs: (1) relapse versus remission, (2) relapse versus controls, and (3) remission versus controls. In 82 of 85 co-occurring genes (96.5%) in naïve T helper cells, the level of DNA methylation was altered according to disease activity, but was not related to disease activity in the 4 genes detected in monocytes.

Therefore, in 82 co-occurring genes in naïve T helper cells, the regulation of DNA methylation was well correlated with the clinical and pathophysiological state. Our genome-wide approach to analyze DNA methylation provides further insight into the pathogenesis of MCNS and indicates potential prediction and diagnostic tool for the disease.

The online version of this article (doi:10.1186/s13104-017-2719-1) contains supplementary material, which is available to authorized users.

• Children
• DNA methylation
• Helper T cell
• Microarray-based integrated analysis of methylation by isoschizomers method
• Minimal-change
• Monocyte
• Nephrotic syndrome

• Biopsy
• Edema/etiology
• Edema/pathology
• Female
• Humans
• Immunosuppressive Agents
• Kidney/pathology
• Middle Aged
• Mycobacterium avium/isolation & purification
• Mycobacterium avium-intracellulare Infection/pathology
• Nephrosis, Lipoid/complications
• Nephrosis, Lipoid/pathology
• Proteinuria/etiology
• Proteinuria/pathology
• Remission Induction
• Treatment Outcome

• Hantavirus
• Hemorrhagic fever with renal syndrome
• Nephropathia epidemica
• Puumala virus

Soluble-lymphocyte subsets (sCD19 + CD23+ B cells and sCD4 + CD25+ T cells), soluble-adhesion molecules (sE-selectin) and interleukin-12 (sIL-12) were assayed to evaluate the pathogenesis of steroid sensitive nephrotic syndrome in 48 patients diagnosed with steroid sensitive nephrotic syndrome (SSNS) in active (AS) and remission stages (RS).

The ratios of soluble CD19 and sCD19 + CD23 increased in patients with AS with respect to the patients with RS and controls (p < 0.05). Increased sCD19 + CD23 ratios were preserved in the patients with RS when compared with the controls (p < 0.05). Moreover, the ratios of sCD4 + CD25 lymphocyte subsets were not significantly different among the groups. Similarly, serum sIL-12 levels were not considerably disparate between the AS and RS. Serum sE-selectin levels were higher in the patients with AS relative to the controls (p < 0.01) and RS (p < 0.05). No significant correlations were noted between sE-selectin and lymphocyte subset ratios, serum sIL-12 and immunoglobulin levels. There was a positive correlation between sE-selectin, triglyceride (r = 0.757, p < 0.0001) and cholesterol (r = 0.824, p < 0.0001) levels in patients with the AS.

The present results indicate that the patients with SSNS appear to have abnormalities in sCD23 + CD19+ cells, defect in T regulatory cell activity, and injury in endothelial cells as indicated by the presence high sE-selectin. These abnormalities might play a role in the pathogenesis of nephrotic syndrome. sIL-12 seems to have no role in pathogenesis of nephrotic syndrome reflecting normal Th1 response.

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.

• Acute Kidney Injury/etiology
• Adult
• Creatinine/blood
• Female
• Finland
• GATA3 Transcription Factor/urine
• Hemorrhagic Fever with Renal Syndrome/complications
• Hemorrhagic Fever with Renal Syndrome/pathology
• Hemorrhagic Fever with Renal Syndrome/urine
• Humans
• Interleukin-6/blood
• Interleukin-6/urine
• Interleukin-8/urine
• Length of Stay
• Leukocytosis
• Male
• Middle Aged
• Prospective Studies
• Puumala virus
• RNA, Messenger/urine
• Risk Factors

• U19 AI057319 NIAID NIH HHS
• U19 AI57319 NIAID NIH HHS

• dna methylation
• nephrotic syndrome
• monocytes
• naive t helper cells
• microarray-based integrated analysis of methylation by isoschizomers (miami) method
• genome-wide
• children