Serum Cytokine Alterations Associated with Age of Patients with Nephropathia Epidemica

Abstract

Nephropathia epidemica (NE) is a zoonotic disease caused by hantaviruses transmitted from rodents, endemic in the Republic of Tatarstan, Russia. The disease presents clinically with mild, moderate, and severe forms, and time-dependent febrile, oliguric, and polyuric stages of the disease are also recognized. The patient's cytokine responses have been suggested to play a central role in disease pathogenesis; however, little is known about the different patterns of cytokine expression in NE in cohorts of different ages and sexes. Serum samples and clinical records were collected from 139 patients and 57 controls (healthy donors) and were used to analyze 48 analytes with the Bio-Plex multiplex magnetic bead-based antibody detection kits. Principal component analysis of 137 patient and 55 controls (for which there was full data) identified two components that individually accounted for >15% of the total variance in results and together for 38% of the total variance. PC1 represented a proinflammatory TH17/TH2 cell antiviral cytokine profile and PC2 a more antiviral cytokine profile with patients tending to display one or the other of these. Severity of disease and stage of illness did not show any correlation with PC1 profiles; however, significant differences were seen in patients with high PC1 profiles vs. lower for a number of individual clinical parameters: High PC1 patients showed a reduced number of febrile days, but higher maximum urine output, higher creatinine levels, and lower platelet levels. Overall, the results of this study point towards a stronger proinflammatory profile occurring in younger NE patients, this being associated with markers of acute kidney injury and low levels of high-density cholesterol. This is consistent with previous work indicating that the pathology of NE is immune driven, with an inflammatory immune response being associated with disease and that this immune response is more extreme in younger patients.

Figure 1

The proportional contribution of each cytokine/receptor to the two principal components: PC1 and PC2.

Figure 2

Frequency and age distribution of PC1 and PC2 in NE and controls. Frequency of PC1 (a) and PC2 (b) distributions in NE and controls. Frequency of PC1 (c) and PC2 (d) distributions based on age of NE and controls. For details of the statistical analysis, see the text.

Figure 3

The relationship of PC1 to PC2 responses. Because of the tight clustering of control values with some overlapping values from patients in the bottom left hand corner of (a). This section is magnified in (b).

Figure 4

Heat map analysis of serum cytokine difference based on age of NE patient.

Figure 5

Measures of pathology in control subjects (green columns, labelled 0) and in patients (white columns, labelled 1-4), according to four ranges of PC1 and PC2. The sample sizes are given in respective columns in the top two panels, while in those below only if they differed from those in the top panel. Ka − 1 = potassium.