Renal Injury in DENV-4 Fatal Cases: Viremia, Immune Response and Cytokine Profile

Abstract

Dengue virus (DENV) infections may result in asymptomatic cases or evolve into a severe disease, which involves multiple organ failure. Renal involvement in dengue can be potentially related to an increased mortality. Aiming to better understand the role of DENV in renal injury observed in human fatal cases, post-mortem investigations were performed in four DENV-4 renal autopsies during dengue epidemics in Brazil. Tissues were submitted to histopathology, immunohistochemistry, viral quantification, and characterization of cytokines and inflammatory mediators. Probably due the high viral load, several lesions were observed in the renal tissue, such as diffuse mononuclear infiltration around the glomerulus in the cortical region and in the medullary vessels, hyalinosis arteriolar, lymphocytic infiltrate, increased capsular fibrosis, proximal convoluted tubule (PCT) damage, edema, PCT debris formation, and thickening of the basal vessel membrane. These changes were associated with DENV-4 infection, as confirmed by the presence of DENV-specific NS3 protein, indicative of viral replication. The exacerbated presence of mononuclear cells at several renal tissue sites culminated in the secretion of proinflammatory cytokines and chemokines. Moreover, it can be suggested that the renal tissue injury observed here may have been due to the combination of both high viral load and exacerbated host immune response.

Brazilian Dengue Virus Type 2-Associated Renal Involvement in a Murine Model: Outcomes after Infection by Two Lineages of the Asian/American Genotype

“…This hypothesis is supported by authors who believe that altered vascular permeability in dengue is caused by immunological host response, rather than by infection of endothelial cells or cell death [84][85][86]. Moreover, our histopathological findings showed hemorrhage foci and small mononuclear cells infiltrates in the cortical area of kidney of the DENV-2 infected mice and corroborates studies carried out with human cases of DENV-3 and -4 infection, and BALB/c mice infected with DENV-3 [17,27,74,75,87].…”

“…The presence of DENV in the kidney has already been demonstrated through the detection of the viral antigen in the tissue cells and in macrophages and monocytes circulating in kidney blood vessels [ 13 , 15 , 17 , 26 , 27 ]. Furthermore, the observation of microtubule reticular structures and dilatation of endoplasmic reticulum in necrotic cells and dense virus-like particles in glomeruli in a transmission electron microscope (TEM), suggested viral infection [ 17 , 28 , 29 ].…”

“…Analysis of kidney samples from DENV-infected human cases revealed parenchyma and circulatory damage [ 17 , 27 ]. Tubular necrosis, evidenced by the presence of pyknotic nuclei of epithelial cells, thickening of the glomerular basement membrane, mesangial proliferation, glomerular congestion and hyalinosis, interstitial area with focal fibrosis, diffuse mononuclear infiltrate and hemorrhage foci in the cortical and medullary regions and the increase in populations of CD68+ and CD4+ cells have been reported [ 27 , 42 , 43 , 44 ].…”

Renal Injury in Dengue Viral Infections

“…A very early study, in 1973, of 24 children presented with abnormal urinalysis in DVI. Proteinuria, glycosuria, ketonuria, occult blood, microscopic hematuria, and an abnormally high number of tubular cells were found in 71, 19,38,38,80, and 90% of the cases, respectively. 5…”

“…It is postulated that a high systemic viral load along with exacerbated host immune response is the cause for renal tissue injury. 19…”