Chronic Kidney Disease
Pathogenetic Aspects
HIVAN and non-HIVAN glomerular diseases are clearly due to HIV infection, but the mechanisms involved in their pathogenesis are far from being completely elucidated. In the glomerulus, podocyte damage has mostly been studied in the course of HIVAN, although these cells are involved in all other HIV-related glomerulopathies as well. In human HIVAN, podocytes display a dysregulated phenotype, reflected by the loss of most specific markers and re-expression of immature proteins, ultimately leading to proliferation and apoptosis.5
Damage to podocytes is thought to be primarily due to direct viral infection and in this respect most knowledge in recent years has come from the analysis of HIV rodent models. The most commonly used animal model is the Tg26 HIVAN mouse model that was generated in 1991. Tg26 mice express a replication-deficient HIV in the skin, skeletal muscle and kidneys. Lower viral messenger RNA (mRNA) levels can be detected in other organs. The kidney pathology of these mice recapitulates HIVAN in a very severe form in the homozygous animal, leading to death before 40 days of age.6
More recently, thanks to the possibility of generating lineage-specific knockout models, several podocyte-specific transgenic animals have been produced that have highlighted the importance of some HIV genes, especially nef and vpr, in HIVAN pathogenesis.7
Besides the
direct viral infection of glomerular and tubular cells, renal HIV-related damage leading to CKD can also be due to cytokines and growth factors aberrantly produced by HIV-infected circulating leukocytes and/or HIV products that act as extracellular mediators. Furthermore, genetic factors have to be taken into account that contribute to organ involvement, variability of histological features and progression to chronic renal failure.
Viral Infection
Although several authors have demonstrated the presence of viral nucleic acids in renal cells, no evidence has been produced so far on the expression of viral products by cells resident in the kidney tissues of HIV-infected subjects. The mechanism by which HIV-1 enters glomerular and tubular cells remains unresolved because renal cells do not express any known HIV-1 receptors. The lack of conventional HIV-1 receptors has prompted many investigators to propose different receptor pathways, such as those using the chemokine C-C motif ligand 3 (CCL3),8 antigen receptor complex9 205).10
the Duffy and the lymphocyte antigen 75 (LY75 or DEC- They have also suggested unconventional modes of viral entry,
including passive transfer of receptors from one cell to another or fusion of tubular cells with HIV-1-infected peripheral blood mononuclear cells and subsequent viral transmission.11,12
Most studies have demonstrated HIV mRNA in podocytes, parietal cells of the Bowman’s capsule and tubular cells, whereas conflicting data have been published about a possible viral infection of mesangial cells.13,14
Development of nephropathy is profoundly influenced by genetic background in animal models. In this field, work by Gharavi’s group has recently led to important discoveries through the identification of a major locus called HIVAN1 on chromosome 3 that is linked to HIVAN development.21
The group has also shown that HIVAN susceptibility
Instead, there seems to be general agreement on the fact that glomerular endothelial cells cannot become infected by HIV. This is despite the fact that numerous endothelial changes can be observed in the glomerulus of both HIVAN and non-HIVAN glomerulopathies and endothelial damage is a recognised major complication in the ART era, leading to a wide spectrum of vascular manifestations.15
Viral Products
Instead of or in addition to direct HIV infection, the action of HIV products shed by the virus and entering the circulation, such as
20
genes belong to a regulated transcriptional network that influences the expression of podocyte molecules, such as Myh9 and Nphs2.22 The relevance of podocyte damage in the pathogenesis of HIVAN has therefore been highlighted once more.
HIV-associated Nephropathy
HIVAN is almost exclusively present in subjects of African descent, with 85–90% of cases being in black patients. The incidence of HIVAN in the US is estimated to be between 3.5 and 12%.23
This percentage
has decreased since the introduction of ART, dropping to 1% in series with good compliance with therapy.24
In fact, inadequate access to
ART can influence the prevalence of HIVAN, demonstrated by the fact that it occurs in developing countries, such as sub-Saharan Africa.25
EUROPEAN NEPHROLOGY
gp120 and Tat, can produce renal cellular damage by several mechanisms that remain incompletely understood. Interaction of tubular cells with gp120 has been shown to induce monocyte recruitment and fibroblast proliferation, contributing to tubulointerstitial damage.16,17
both events likely
In podocytes, exogenous application of Tat has been shown to bind to heparan sulphate proteoglycans on the cell surface, increase cell proliferation,18
the actin cytoskeleton.19
decrease nephrin expression and profoundly rearrange Further studies are certainly needed to
assess the functional effects of these viral products in vitro, and especially in vivo, because the currently available animal models, being transgenic models in which the infection is bypassed, cannot fully provide this kind of information.
Cytokines and Growth Factors
For the same reason, current animal models are not the most suitable for developing a deep understanding of the role played by immune mechanisms and by infected lymphocytes and macrophages infiltrating the kidney in the pathogenesis of kidney damage.
In
humans, HIV infection leads to an immune response with antibody production and a wide array of circulating cytokines and growth factors that can justify the onset of immune-complex-mediated glomerular diseases and inflammatory renal infiltration.
From this point of view, the pathogenesis of HIV-related immuno- mediated renal affections seems better explained than HIVAN and non-immune glomerulopathies, such as non-collapsing focal segmental glomerulosclerosis (FSGS) and minimal change disease. Several major points remain unclear, however, such as whether glomerular damage in immune-complex nephritis is due to passive trapping of circulating immune complexes or to in situ deposition of antibodies against viral antigens.
Genetic Aspects and the Relevance of Podocyte Damage
A role for host susceptibility factors is demonstrated by the distribution of different forms of glomerular diseases, with increased prevalence of non-HIVAN glomerulopathies in Caucasians and a high prevalence of HIVAN among patients of African ancestry. The latter case is likely to be due to variations in the MYH9 gene.20
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100