Looking into the past and future of human immunodeficiency virus nephropathy.

Human immunodeficiency virus-infected patients are could be argued, however, that if patients with early at risk of developing several types of acute and chronic renal disease were found, perhaps some of them would renal diseases [1–3]. Among them, HIV-associated nehave had CD4 cell counts closer to normal. Because phropathy (HIVAN) has received significant attention the criteria for renal biopsy appeared to include elevated because it is believed to be caused by the direct effects serum creatinine, these patients would have been missed. of HIV-1 on renal cells. Typically, HIVAN is defined as Thus, is HIVAN a late manifestation of HIV infection, a combination of several pathologic renal lesions that or was the diagnosis made too late? The authors do point include a collapsing form of focal segmental glomeruloout, however, that other studies have included patients sclerosis, glomerular visceral epithelial cell hypertrophy, with earlier renal disease, and they, too, have low CD4 and prominent tubulointerstitial infiltration with edema, cell counts. Therefore, what are the early stages of fibrosis, and microcystic tubule dilation [1–3]. These HIVAN? Based on results derived from HIV-transgenic changes lead to renal enlargement and a rapid progresmice, the course of HIVAN could be divided in two sion to end-stage renal disease. The mechanisms by stages [5]. The first stage is characterized by the induction which HIV-1 induces renal lesions are not clearly deof renal injury by HIV-1 genes, which is manifested clinifined, and it is possible that reviewing the natural history cally by moderate proteinuria but normal serum creatiof HIVAN may help to elucidate the most relevant nine levels. The second stage could be defined by the pathogenic events producing HIVAN, as well as other rapid regenerative/proliferative renal response leading renal diseases related to HIV-1 infection. to kidney enlargement and rapid progression to endSince the early years of the AIDS epidemic, some stage renal disease. Although the first stage is probably studies have suggested that HIVAN could be an early driven by HIV-1 genes, the second stage is more likely manifestation of the HIV infection [1, 2]. In this issue driven by cytokines or growth factors released by injured of Kidney International, Winston, Klotman and Klotman or regenerating renal cells. In patients with HIVAN, review the timing for the diagnosis of HIVAN under the these two stages are less clearly defined, as continuous current definition for AIDS cases that the Centers for changes in viral replication, the host immune response Disease Control established after 1993 [4]. They conclude to HIV-1 or other infectious agents, and the recruitment that an overwhelming majority of HIV-infected patients of HIV-1–infected cells in the kidney play additional develop HIVAN during the late stage of HIV infection. roles throughout the course of the disease. However, In addition, they show that 50% of HIV-infected patients HIV-infected children may undergo long periods of who had a renal biopsy because of azotemia and/or promoderate proteinuria (one to two years) before develteinuria (more than 1 g per 24 hr) revealed histologic oping nephrotic syndrome or renal failure [6, 7]. During features consistent with other renal diseases. this time, the presence of microcysts in the urine sediThis study raises several interesting issues. First, it ment, persistent proteinuria, and enlarged echogenic kiddemonstrates the importance of doing a renal biopsy to neys in renal sonograms are useful clinical markers to confirm the diagnosis of HIVAN and suggests that new predict the presence of HIVAN [7]. Nevertheless, even clinical entities generated by other renal diseases that considering these clinical markers of HIVAN, our expedevelop in the setting of HIV infection may be on the rience in HIV-infected children support the notion that way. Thus, additional information is needed to define HIVAN is a late manifestation of HIV infection [7]. how HIV-1 modulates the outcome of other classic renal Thus, Winston et al’s suggestion that changes in viral diseases. tropisms and host response that occur during the late Second, Winston et al stress the concept that HIVAN stages of HIV infection may play a relevant pathogenic is a late, not early, manifestation of HIV infection. It role in HIVAN may be clinically relevant. For example, it is possible that regenerating renal cells may up-regulate the synthesis of chemokine receptors and cell surface