First report of collapsing variant of focal segmental glomerulosclerosis triggered by arbovirus: dengue and Zika virus infection

Abstract

Background: The collapsing variant of focal segmental glomerulosclerosis (FSGS) is the most aggressive form of FSGS and is characterized by at least one glomerulus with segmental or global collapse and overlying podocyte hypertrophy and hyperplasia. Viruses can act as aetiological agents of secondary FSGS. This study aims to establish an aetiological link between dengue virus (DENV) infection and the collapsing variant of FSGS and to analyse possible influences of the apolipoprotein 1 (APOL1) gene risk alleles on the disease.

Methods: Biopsies and medical records were gathered from 700 patients of the Instituto de Nefropatologia, Belo Horizonte, Brazil. Screening for the collapsing variant of FSGS was performed and serological, immunohistochemical, tissue polymerase chain reaction (PCR) and genetic analysis were conducted.

Results: Eight patients were identified with positive DENV serology and negative serological and/or tissue markers for hepatitis B virus, hepatitis C virus, Epstein-Barr virus, human immunodeficiency virus, cytomegalovirus and parvovirus B19. In PCR analysis, six patients had positive markers for DENV strain genetic material, one patient had positive markers for co-infection of Zika virus (ZIKV) and DENV and one patient had positive markers only for ZIKV infection. Six of the eight patients did not show risk alleles of the APOL1 gene. One patient had only one risk allele (G1) and the sample from another did not contain enough DNA for genetic analysis to be performed.

Conclusions: This study provided strong evidence that DENV can infect renal tissue and possibly functions as a second hit to the development of the collapsing variant of FSGS. Nonetheless, this study also highlights the possible implication of ZIKV infection in FSGS and supports the argument that risk alleles of the APOL1 gene may not be implicated in the susceptibility to FSGS in these patients.

Keywords: arbovirus; chronic kidney disease; dengue infection; focal segmental glomerulosclerosis; renal histopahology.

FIGURE 1

Illustrative schema of patients and biopsies selection of the study. Among 13 patients with focal segmental glomerulosclerosis (FSGS) and positive serology only for Dengue virus (DENV) infection, 11 showed collapsing FSGS. Eight among 11 cases of collapsing variant of FSGS had renal tissue positivity for virus of Flavivirus genus, being six positive for DENV, one for Zika virus (ZIKV) and one for both DENV and ZIKV.

FIGURE 2

(A) Bowman Space dilatation with glomerular collapsed and Podocyte hyperplasia. (B) Rim of crowed and reactive podocytes resembling a celullar crescent with collapsed capilar loops (Jone’s stain 40X). (C) Several glomeruli showing collapsing glomerulopathy and tubular dilatation (PAS stain 10X). (D) Sloughed cells intubules. (E and F) Immunofluorescence showing focal trapping of mesangial C3 and IgM (40X).

FIGURE 3

Transmission Electron Microscopy. (A) Diffuse wrinkling of the glomerular basement membrane (M) with electron-dense protein reabsorption droplets and widespread effacement of the podocyte (P) foot process (see arrows). Bowman’s capsule (C). (B) Detail of the foot process effacement (see red arrows).

FIGURE 4

DNA sequence chromatograms of the APOL1 gene showing a homozygous individual with the wild type for (A) rs73885319 (p.S342G), (B) rs60910145 (p.I384M), and rs71785313 (p.NYK388K) variants.

FIGURE 5

The scheme illustrates the immigration flux from Africa to America. The region of biggest prevalence of the APOL1 gene risk variant is evidenced in red, along the territories of Sierra Leone and the previously called Golden Coast. In blue and green are indicated, respectively, the Brazilian regions of biggest prevalence of African immigrants that came from the same African region as the USA (blue) and from the previously called Angola Coast.