hantavirus infection nephropathy

  • 9 min read
  • Feb 10, 2020

Hantavirus Nephropathy | American Society of Nephrology
Hantavirus Nephropathy | American Society of Nephrology

rat-borne pathogenic hantaviruses cause in general human infections involving the peripheral vascular bed and greatly affect their permeability. We describe a male patient 30 years with clinical symptoms characteristic of the conventional five phases of dengue fever with renal syndrome after severe hantavirus infection rarely with Puumala strain. Renal biopsy in this situation usually indicates acute hemorrhagic interstitial nephritis, especially pronounced in the outer medulla. Hantaviruses not cytopathic for most of the cells and their interaction with endothelial cells that activate the immune mechanisms play a key role in the pathogenesis of vascular dysfunction characteristic of this disease.

A 30 years old man was taken to hospital with a history of 5-d flu-like symptoms: headache, chills, nausea, vomiting, back pain, arthralgia, myalgia, and blurred vision. In previous months, he has been closely related to rodents in the village of Dobrava, which is filled with two strains endemic hantavirus, Puumala and Dobrava. On admission, she was hypotensive with a BP of 85/55 mmHg and a serum creatinine level of 382 umol / L (normal 44-97 umol / L). On day 6, he became oliguric, drowsiness, tachypnic, and tachycardia. On physical examination found eyelid edema and conjunctival injection with bleeding. Laboratory tests revealed a white blood cell count of 21,600 / mm3. A 34,000 platelets / mm3, increasing 65.7 s partial thromboplastin time, and fibrin degradation product of 24.0 mg / L (normal <1 mg / L) suggest disseminated intravascular coagulation. Urinalysis showed 1.3 g / d proteinuria and erythrocyte too many to count. survive severe oliguria, serum creatinine increased in the 7-640 umol / L, and on the 9th day that hemodialysis patientstarted for 6 days in a row. Urine output is gradually rising, and he became polyuric in the third week of the disease. The patient recovered and was discharged after 4 weeks of treatment in the hospital with all the normal laboratory findings except for a slight increase in serum creatinine level of 115 umol / L and mild hematuria. serological tests performed on day 6 and 19 showed increased more than fourfold IgG titer by immunofluorescence assay and IgM capture ELISA titer by using antigen prepared from Vero E6 cells infected with strain 76-118 Hantaan, Seoul strain SR-11, Puumala tension Hällnäs B, or Dobrava 3970. prototype strain confirmed acute infection with Puumala focus reduction neutralization test, the most sensitive method available for distinguishing hantaviruses.

light microscopy of renal biopsy needle on day 10, covering the medulla outside and the cortex and contains 11 glomeruli, features showed mild to moderate acute injury tubular cortex, approximately 40% of interstitial edema, and scattered, mononuclear cell infiltrate dominated () .Electron peritubular capillary microscopy revealed discrete injury with effusion fluid and plasma recently and end extravasation of erythrocytes into the interstitium (). glomerular capillary endothelial revealed some swelling and edema by reducing the subendothelial rare fenestration, along with traces of glomerular IgM was found by immunofluorescence. In a biopsy of the cylindrical outer medulla, histomorphologic changes more pronounced and distinctive area dominated by interstitial hemorrhage (). Compressed tubule floating and barely visible lines of dense peritubular capillaries can be seen in the sea were made mostly by large extrusion erythrocytes, with only a rare mixture of inflammatory cells (, inset). Focal tubular dilation and discrete damage to tubules and peritubular capillaries are rarely observed. Immunophenotyping showed that the majority of inflammatory cells are sparse interstitial CD8 + cytotoxic T lymphocytes (CTL) and CD68 + macrophages (). Findings haemorrhagic acute interstitial nephritis biopsies with lesions characteristic distribution of the most prominent support the diagnosis of hantavirus nephropathy.

Needle Biopsy showed histomorphologic changes in the kidney of a male patient 30 years in acute oliguric phase Puumala hantavirus infection. (A) At low magnification, large interstitial hemorrhage was present in outer medulla (left cylinder), whereas only mild acute tubular injury, interstitial edema and inflammatory cell infiltration seen in the cortex (right cylinder). high magnification (inset) of the outer medulla of kidney showed a barely visible outline of wide, blood-engorged peritubular capillaries (arrows) as well as abundant interstitial hemorrhage appears as a floating sea of ​​erythrocyte tubules separated and compressed (periodic acid methenamine silver-Azan). micrograph (B) Electrons from the renal cortex showed interstitial edema and extravasated fresh, well-preserved erythrocytes (*), as well as two dysmorphic red blood cells are affected by hemolysis (arrows; OsO4, uranyl acetate and lead citrate). (C) In the medulla hemorrhagic, quite sparse irregular interstitial infiltrates of inflammatory cells, consisting predominantly lymphocytes, CD8 + T brown stained and red-stained CD68 + monocytes / macrophages (sequential immunostaining dual use Ventana mAb against CD8 [clone C8 / 144B] and UltraView DAB detection kit and then mAb to CD68 [clone KP-1] and UltraView Red detection kit, with hematoxylin counterstain).

More than 30 different strains of hantaviruses have co-evolved for thousands of years around the world, each with a specific rodent host associated with certain geographic area.- Human infection by inhalation of aerosols of rodent dirt hosting> 20 hantaviruses pathogen has been identified to date, resulted in two life-threatening clinical syndrome. All Old World hantaviruses cause hemorrhagic fever pathogens with renal syndrome (HFRS), a common infection of varying severity, because in general acute renal failure caused by hantavirus nephropathy ().

hantaviruses major cause of human disease in the Old and New World and hostsa mice their natural

virus prototype Hantaan cause HFRS around 150,000 people every year in China, Far East Russia, and Korea , with a mortality rate of 5 to 15%. The genetic and serological closely related Dobrava virus, first isolated in Slovenia, led to the same severe HFRS mainly in central and southeastern Europe. virus Puumala, which belongs to another, the lineage of the two trees hantavirus phylogenetic, affects about 5,000 people per year across Europe, with the mortality rate is low (<1%) and a milder form of HFRS., There are exceptions, such as the case presented here and other reported cases of fatal autopsied. All New World hantaviruses pathogens, including prototype Sin Nombre virus was isolated in 1993, belongs to the lineage and the second leading cause hantavirus pulmonary syndrome (HPS), which affects mainly the lungs, with a mortality rate of> 50%. ,,, Five chronological phases have clinically studied and reported in patients with severe HFRS (). mechanisms are frequently severe proteinuria in HFRS is still unclear. tubular proteinuria may be only partially contribute, and our hypothesis of a causal relationship with the glomerular endothelial cell injury is speculative.

The main clinical manifestations for five phases of HFRS. Data refer to a severe form of HFRS caused by Hantaan and Dobrava virus. In a milder form of HFRS, also called nephropathia epidemica, mostly caused by Puumala virus, generally less obvious clinical phase, and bleeding, severe hypotension, and shock are rare. Adapted from reference.

Knowledge of pathomorphology of hantavirus nephropathy in severe forms of HFRS coming from autopsy studies detail during the Korean War, when the cause is still unknown. Studies of biopsy has been largely limited to a series of cases affected by a mild form of HFRS caused by Puumala virus.- Despite the injury severe peripheral vascular permeability is apparently common, lung is the main target in the HPS, and hantavirus nephropathy dominate both in severe and mild form of HFRS.,, Hantaviruses which endotheliotropic and Zaki et al., using all available techniques include immunohistochemistry with the effective area in the home mAb GB04-BF07, provide evidence that at least in HPS, hantavirus is present in endothelial cells of small blood vessels in many organs, especially the lungs and some renal borders, especially in capillary interstitial cord and rarely in tubular epithelial cells. There is less convincing research to other mAb demonstrated that pathogenic changes in HFRS appear exclusively in tubular epithelial cells, particularly in the electron microscopy studies medulla.- of HFRS, including our analysis, failed to provide convincing evidence of the presence of hantavirus particles in t kidneysissue. This is probably due to the low number of hantaviruses in the kidneys: In fatal cases we HFRS, Dobrava hantavirus RNA was detected only in autopsy samples from renal medulla with highly sensitive reverse transcriptase-PCR and identified by nucleotide sequence analysis. Our study provides evidence of low-level infection that approximately the entire peripheral vascular beds kidney, including cortical glomeruli and peritubular capillaries, involved in hantavirus nephropathy; However, so far the most dear vascular severe is the medullary outside, especially stripe outside, present in the early phase of the interference congestion and permeability, and of the transition to phase oliguria with stasis severe blood accompanied by leakage, bleeding interstitial widespread, severe endothelial degenerative changes and necrosis sometimes anemia in the medulla deeper. ,,,, in line with our results of immunophenotyping cells, CTL and macrophages are the interstitial inflammatory cells dominant.

histomorphologic features of hantavirus nephropathy and diagnostic characteristics with renal biopsy when an adequate sample of the outer medulla available. Only a few more dengue fever virus and viral interstitial nephritides where bleeding in the kidney have been reported, and they do not have the same histotopography HFRS. Vasomotor acute tubular injury and / or hemostatic disorders can also contribute to pathogenesis.

We conducted a comparative study of 10 kidney biopsies and autopsies of patients who had a four HFRS infection with hantavirus Dobrava and 10 kidney biopsies of patients with HFRS infection with Puumala virus without death (unpublished data). There is no qualitative difference, but there are quantitative differences in histopathology, virus-infected patients with renal average Dobrava be more affected, especially related to the intensity and extent of the injury medullary interstitial capillaries, congestion, hemorrhage, and tubular necrosis (and).

Plot depicts a hypothetical pathophysiology of histomorphologic most striking features shown in the electron micrograph of the medulla of kidney biopsies obtained from patients with severe acute Dobrava hantavirus nephropathy. severe congestion (A, arrow) and focus, excessive necrotizing (B *) injuries that damage the peritubular capillaries (B, arrows) revealed major changes in permeability and leakage resulting from the blood fluid and cells into the interstitium (A and B ). cytokines involved are IL-1, IL-2, IL-6, IL-10, IL-12, TNF-α, IFN-γ, and vascular endothelial growth factor (VEGF) and the chemokine RANTES, monocyte chemoattractant protein-1 (MCP-1), IP-10, and IL-8. ICAM-1, an adhesion molecule-1; PECAM-1, platelet-endothelial cell adhesion molecule-1; VCAM, vascular cell adhesion molecule-1.

It is also noted that hantaviruses are not cytopathic for most cells. They replicate in macrophages and endothelial cells, enter host cells through integrin β3 surface molecules. Both hantaviruses pathogenic and non-pathogenic has the same tissue tropism, but recent studies show important differences in the response of endothelial cells genes induced by pathogens or pathogenic hantaviruses, as well as the induction of genes unique to HPS- and HFRS-producing hantaviruses.

association mild or severe clinical course of disease with certain HLA alleles suggests a role for the host immune response., Hantaviruses induce innate immune response and the adaptive immune response humoral and cellular. Increased titers of virus-specific IgM, IgA, IgG and IgE antibodies and immune complexes were detected in the serum for hantavirus infection. The mechanism of immune complex deposition once suggested to play a role in the pathogenesis, but this was not confirmed by later studies, including our results. ,, antibody-dependent cellular cytotoxicity and complement activation likely due to effector mechanisms by antibodies to hantaviruses. The level of activation of the classical pathway complement correlates with the clinical course of HFRS.

CTL dominate in renal interstitial inflammatory cell infiltrate the hantavirus disease. They seem to have an important role in the eradication of the virus associated with apoptosis of infected cells, and also in tissue injury. Furthermore, CTL and infected endothelial cells, macrophages, and dendritic cells produce a variety of cytokines and chemokines, which contribute to the pathogenesis of hantavirus disease (). Significantly increased plasma levels of IFN-γ, TNF-α, IL-2, and IL-6 was detected in the acute phase of the disease hantavirus, and the level of TNF-α, one of the most pro-inflammatory cytokine importantly, correlate with disease severity., Improved TNF-α expression, as well as an adhesion molecule-1, vascular cell adhesion molecule-1 and platelet-endothelial cell adhesion molecule-1, which is present in peritubular region of the distal nephron in the kidney biopsies of patients with HFRS Puumala virus-induced. In vivo studies have also confirmed the important role of TNF-α, suggesting that exposure to high doses of these cytokines cause shock, increased capillary leakage, and death. Some studies show that an increase in vascular permeability is also associated with elevated levels of vascular endothelial growth factor produced by endothelial cells and macrophages infected.

Infection with hantavirus causes damage to the endothelial cell function and, through the induction of cytokines, chemokines, and cellular receptors, modulating the immune response, which seems to have an important role in the pathogenesis of hantavirus disease.

no.

We thank Prof. Dr. Andrej Bren to provide clinical data and Prof. Dr. Tatjana Avšič-Županc right to hantavirus serotypes and helpful discussion. We also thank Dr. Anastazija Hvala for electron micrographs, Ziga Kušar, BSc, for technical support is excellent, and the staff MEA-European Lab Applications of Ventana Medical Systems SA for assistance in the double immunostaining of kidney biopsy specimens us.

Published online before print. , Date of publication available at

© 2020 American Society of Nephrology

Print ISSN – 1046-6673 Online ISSN – 1533-3450

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