Controversies in the pathogenesis of HIV-associated renal diseases

Abstract

The two most common HIV-associated renal diseases, HIV-associated nephropathy and HIV immune-complex kidney disease, share the common pathologic finding of hyperplasia within the glomerulus. Podocyte injury is central to the pathogenesis of these diseases; however, the source of the proliferating glomerular epithelial cell remains a topic of debate. Parenchymal injury has been linked to direct infection of renal epithelial cells by HIV-1, although the mechanism of viral entry into this non-lymphoid compartment is unclear. Although transgenic rodent models have provided insight into viral proteins responsible for inducing renal disease, such models have substantial limitations. Rodent HIV-1 models, for instance, cannot replicate all features of immune activation, a process that could have an important role in the pathogenesis of the HIV-associated renal diseases.

Figure 1

Renal biopsy sample from a patient with HIVAN. HIV-1 messenger RNA is detected via an in situ hybridization methodology that leads to the formation of a purple stain. In infected cells, viral messenger RNAs transcribed from viral DNA are primarily found in the cytoplasm. a Hybridization-positive tubular epithelial cells and immune cells have infiltrated the interstitium (60× magnification). b Viral messenger RNAs are also present in podocytes and parietal epithelial cells (100× magnification). Abbreviation: HIVAN, HIV-associated nephropathy.

Figure 2

The interplay of environmental (red) and genetic (blue) factors in HIV-associated renal diseases. Of central importance is HIV-1 infection, which occurs in both renal epithelial cells and immunocytes resident and infiltrating the kidney. Although their effect is not fully understood, genetic factors also contribute to pathogenesis, possibly by determining susceptibility to renal cell infection or cell injury response. In HIVICK, and perhaps also HIVAN, immune and inflammatory pathways have a role in disease onset, progression, and severity. Top panel shows typical HIVAN pathology consisting of collapse of the glomerular tuft with segmental areas of sclerosis (thickened basement membranes) and proliferation of epithelial cells adherent to both the tuft and Bowman’s capsule. Microcysts with proteinacious casts can be seen in adjacent tubules. Bottom panel is typical pathology of HIVICK with global sclerosis, mesangial expansion, and hypercellularity encompassing the tuft and Bowman’s capsule. For more detailed information on the pathology of these HIV-associated renal disease, please see an accompanying article in the series. Hematoxylin and eosin stain, both images 60X magnification. Abbreviations: HIVAN, HIV-associated nephropathy; HIVICK, HIV-immune-complex kidney disease..