A urinary biomarker profile for children with HIV-associated renal diseases

Abstract

Human immunodeficiency virus (HIV)-infected children are at risk of developing several types of renal diseases, including HIV-associated nephropathy (HIVAN), which is usually seen during late stages of infection in children with a high viral load. This disease is defined by the presence of proteinuria associated with mesangial hyperplasia and/or global–focal segmental glomerulosclerosis combined with microcystic transformation of the renal tubules. Because HIVAN can have an insidious clinical onset, renal biopsy is the only definitive way of establishing a diagnosis. Given the risk of performing this procedure in HIV-infected children with other AIDS-defining illness, we sought to identify informative biomarkers such as growth factors in the urine of 55 HIV-infected children that might be predictive of the extent and activity of the renal lesions characteristic of HIVAN. We found that the levels of epidermal growth factor were lower in the urine of children with renal disease, whereas levels of fibroblast growth factor-2 and metalloproteinase-2 were higher as compared with those levels in infected children without renal disease. Similar changes were observed in HIV-Tg26 mice correlating with the progression of renal disease in this model of HIVAN. Our findings suggest that this urinary growth factor profile may be useful in facilitating the diagnosis of HIV-infected children at risk of developing HIVAN when interpreted in the appropriate clinical setting.

The Basic Domain of HIV-Tat Transactivating Protein Is Essential for Its Targeting to Lipid Rafts and Regulating Fibroblast Growth Factor-2 Signaling in Podocytes Isolated from Children with HIV-1–Associated Nephropathy

“…[47][48][49] In children with HIVAN, the urinary levels of MMP-9 are increased in correlation with the progression of their renal disease. 14,16 Therefore, because MMP-9 facilitates the release of FGF-2, 34 our findings may provide an alternative mechanism by which Tat can regulate the activity of FGF-2 in podocytes.…”

“…51 Thus, differentiated podocytes that are forced to re-enter the cell cycle under the influence of Tat and FGF-2 may be unable to divide and could detach or undergo apoptosis. Considering that FGF-2 is accumulated in the circulation, glomeruli, and urine of children with HIVAN, 13,14,16,17,36 it is tempting to speculate that the podocytes carrying the genetic risk variants that predispose to HIVAN 52,53 may be more sensitive to this pathogenic mechanism. In support of this notion, we found that both Tat and FGF-2 can precipitate the development of HIVAN in HIVTg 26 mice.…”

“…Nonetheless, children may be more sensitive to the renal accumulation of FGF-2, because their kidneys are growing, and they have high expressions of HSPG, MMPs, FGF receptors, and binding proteins and higher plasma and tissue levels of FGF-2 relative to all other HIV-1 proteins. 13,14,16,17,36 They also develop more severe immunosuppression and higher viral loads, leading to additional secretion of Tat and inflammatory cytokines that release more FGF-2. 6,34 Moreover, our data did not rule out the possibility that Tat, acting through the release of systemic cytokines that upregulate the expression of HIV-1 genes through NF-kB activation, may play an additional role in HIVAN as well.…”

“…Tat Basic Domain Modulates FGF-2-Induced pERK, Rho-A, and pMLC 2 in Cultured Podocytes Because FGF-2 is accumulated in the kidney of children with HIVAN, 13,14,16,17,36 we explored how the Tat basic domain modulated FGF-2 signaling in podocytes transfected with Tat-WT-HIVAN or Tat-BDM1-HIVAN. As shown in Figure 6, we found that Tat-WT-HIVAN, alone or combined with FGF-2, induced a more significant activation of pERK, Rho-A, and pMLC 2 compared with Tat-BDM1-HIVAN.…”

“…[6][7][8] A concentration of Tat within the range detected in sera of HIV-infected patients 9,10 can cause glomerular permeability changes in vivo 11 and induce the proliferation of cultured podocytes by stimulating the release of fibroblast growth factor-2 (FGF-2). 12 Indeed, high plasma, kidney, and urinary levels of FGF-2 are detected in children with HIVAN, 13,14 and FGF-2 is accumulated in the kidney of HIV-Tg 26 mice with renal disease. [15][16][17] Overall, these studies suggest that both Tat and FGF-2 may play a role in the pathogenesis of childhood HIVAN.…”