Emerging Paradigms in the Renal Pathology of Viral Diseases

Abstract

This review considers recent information that illuminates pathogenetic mechanisms that involve three of the major viral infections that cause renal injury in the form of HIV-associated nephropathy, polyoma virus nephropathy, and hepatitis C virus-associated glomerulonephritis.Clin J Am Soc Nephrol 2: S6 -S12, 2007. doi: 10.2215/CJN.00280107 HIV-Associated NephropathyA nephropathy that is associated with HIV infection was identified soon after the epidemic of HIV/AIDS first became recognized in the early 1980s. HIV-associated nephropathy (HIVAN) is a combined glomerular and tubular injury that is characterized by a collapsing glomerulopathy (CG) with collapse of glomerular capillary structures and a striking hyperplasia of podocytes, microcystic transformation of renal tubules, and concomitant and likely nonspecific interstitial inflammation and fibrosis consequent to the glomerular and tubular injuries (Figure 1). From a pathology standpoint, three major areas of investigation have led to a deeper understanding of this lesion.The first of these addresses the issue of whether HIVAN is a direct consequence of viral infection of the renal parenchyma or is a secondary consequence of systemic infection. Cohen et al.(1) first reported the presence of HIV RNA in podocytes as revealed by in situ hybridization (ISH) in 1989, a finding that was supported by microdissection studies of Kimmel et al. (2). These studies were difficult to validate because of the failure of others to replicate these findings using conventional techniques of ISH, the inability to demonstrate the presence of viral peptides in renal parenchymal cells by immunohistochemistry, and the inability to demonstrate appropriate receptors for viral entry into cells, namely CD4 and the chemokine receptors CXCR4 or CCR5, on renal parenchymal cells (3). This created a conundrum in that a mechanism for viral entry into renal cells could not be defined. Some but not all of the difficulties were resolved by a more sophisticated form of ISH, which is based on a technique that detects forms of viral DNA that are characteristic of replicating virus (4 -6). With these techniques, it was possible to substantiate the findings of Cohen et al. and convincingly demonstrate HIV infection of podocytes and tubular epithelial cells.A second key development concomitant with the demonstration of HIV infection of human renal epithelial cells was the development of murine models of HIVAN. The best studied of these involves the Tg26 mouse: Mice are made transgenic for a nearly whole-length HIV virus but with a deletion of HIV gag and pol genes to render the virus nonreplicative (7). Studies of these mice, largely by the group of Klotman and their collaborators, have established that expression of HIV genes, presumably modeling the events of renal HIV infection, is sufficient to produce a renal injury in the mouse that is similar to HIVAN in humans. Studies in which kidneys from transgenic mice were transplanted into wild-type controls demonstrated that renal expression of HIV gene...

Incidence and Predictors of Acute Kidney Injury in an Urban Cohort of Subjects with HIV and Hepatitis C Virus Coinfection

“…Although a few reports of immunohistochemical localization of HCV antigen in renal tissue have been published, results have not been consistently demonstrated. 16,17 Although in our study, higher HCV VL and genotype were not associated with AKI, these findings add important information to currently available data as other epidemiologic studies examining the relationship between HCV and renal disease have not included HCV VL or genotype data. [11][12][13][14] In addition to HIV/HCV coinfection and decompensated liver cirrhosis, cocaine but not heroin use was strongly associated with AKI.…”

“…In contrast to findings that higher HIV VL is associated with increased risk of AKI, we did not find an association between HCV VL and AKI incidence in our analysis. While several studies have demonstrated that HIV infection may be linked to renal disease through direct viral infection of renal parenchyma, 16 a similar mechanism has not been demonstrated for HCV infection. HCV has been linked to several types of glomerular lesions including membranoproliferative glomerulonephritis (MPGN) and membranous glomerulopathy.…”

Treatment of Hepatitis C-Mediated Glomerular Disease

“…Besides MPGN, other forms of glomerular disease have been described in patients infected with HCV including IgA nephropathy, membranous nephropathy (MN), postinfectious glomerulonephritis, thrombotic microangiopathies, focal and segmental glomerulosclerosis and fibrillary and immunotactoid glomerulonephritis [19,20,21,22,23,24,25,26,27,28] (table 1). In an autopsy series of 188 consecutive patients with HCV, Arase et al [29] reported that a MPGN was present in 11%, MN in 2%, and a mesangial proliferative glomerulonephritis in 17%, while 45% of the cases showed no evidence of glomerular involvement.…”

Hepatitis C Virus Associated Glomerulonephritis

“…In HCV infection, the cryoglobulins are almost always of mixed type, with type 2 (monoclonal rheumatoid factor usually IgM kappa) more common than type 3 (polyclonal rheumatoid factor) (Miller and Howell, 2000). Possibly, IgM directed against epitopes of the HCV envelope cross-reacts with IgG, forming the rheumatoid factor (Alpers and Kowalewska, 2007). Thus, the cryoglobulins in HCV infection are composed of HCV RNA and/or proteins, complexed with anti-HCV IgG, in turn complexed to IgM rheumatoid factor.…”