Unraveling a mechanism underlying hepatitis E-associated kidney disease : Discovery of HEV ORF2 capsid protein-associated immune complex glomerulonephritis.

BACKGROUND AND OBJECTIVE: Hepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic manifestations, particularly renal disease. While the underlying pathomechanisms are still largely unknown, these manifestations are thought to develop either directly, i.e., by HEV infection of the respective organ, or indirectly, i.e., via immunologic reactions. Herein, we describe the development of de novo immune complex-mediated glomerulonephritis (GN) associated with the glomerular deposition of a newly described form of the HEV open reading frame 2 (ORF2) capsid protein in patients with chronic or acute hepatitis E. METHODS: We performed immunostaining, electron and deconvolution microscopy, and laser-capture microdissection combined with mass spectrometry to specifically investigate the glomerular compartment. RESULTS: In a kidney transplant recipient with chronic hepatitis E, we show that GN developed in parallel with increasing glomerular deposits of the HEV ORF2 protein, which significantly colocalizes with IgG, thus forming immune complexes. Interestingly, the glomerular HEV ORF2 protein does not correspond to the expected secreted and glycosylated form of the viral capsid protein but rather has the molecular weight of a truncated non-glycosylated form. Importantly, it is not associated with HEV RNA and, in contrast to the situation in liver cells, no productive HEV infection of kidney cells is detected. Patients with acute hepatitis E show similar but less pronounced deposits. Our results establish a link between the production of HEV ORF2 protein and the development of hepatitis E-associated GN. CONCLUSION: The formation of glomerular IgG-HEV ORF2 immune complexes discovered here provides a mechanistic explanation of how the hepatotropic HEV can cause variable renal manifestations. These findings directly provide a tool for etiology-based diagnosis of hepatitis E-associated GN, establish hepatitis E-associated GN as a distinct entity, and suggest therapeutic implications.