Microcystic Tubular Dilatation Research Articles

Dual Glomerular Lesion in Hiv Patient

HIV-associated nephropathy (HIVAN), the classic kidney disease associated with HIV infection, was first described in 1984 as a complication of AIDS although HIVAN may also occur in patients with less advanced HIV infection or following acute seroconversion Histologically, HIVAN is a collapsing form of focal segmental glomerulosclerosis (FSGS) accompanied by microcystic tubular dilatation and interstitial inflammation. HIV-immune complex kidney disease (HIVICK). Other immune complex diseases may also occur in HIV-infected patients, including IgA nephropathy and postinfectious glomerulonephritis, and are best diagnosed as those specific entities The pathophysiological mechanism of HIVAN injury is mediated by direct infection of renal epithelial cells by HIV, expression of intrarenal viral genes, and dysregulation of host genes by modulating cell differentiation and the cell cycle. In contrast, kidney disease by HIV immune complexes (HIVICK) involves a different immune mechanism with antibody deposits within glomerular structures. Both entities progressively present different degrees of proteinuria and progressive decrease in the glomerular filtration rate, depending on the commitment or histology suffered by the patient. In this case reports patient with clinical picture of 3 months of evolution of temporo-spatial disorientation and alteration of the state of consciousness associated with hyperthermia. We perform neuroimaging without alterations, a lumbar puncture performed with evidence of an infectious process by coconuts + in the GRAM of the cerebrospinal fluid, normochromic normocytic anemia and renal failure, sub nephrotic proteinuria, glomerular hematuria, HIV positive, recount of normal CD4, renal biopsy with diagnosis of immune-mediated glomerulonephritis (IgG and C3), in the immunofluorescence (HIVICK) and with membrano pattern proliferative and in two glomeruli focal segmental sclerosis collapsing variant (HIVAN)is observed.

Inhibition of apoptosis signal-regulating kinase 1 mitigates the pathogenesis of human immunodeficiency virus-associated nephropathy.

Chronic kidney disease (CKD) is a common cause of morbidity and mortality in human immunodeficiency virus (HIV)-positive individuals. Among the HIV-related kidney diseases, HIV-associated nephropathy (HIVAN) is a rapidly progressive renal disease characterized by collapsing focal glomerulosclerosis (GS), microcystic tubular dilation, interstitial inflammation and fibrosis. Although the incidence of end-stage renal disease due to HIVAN has dramatically decreased with the widespread use of antiretroviral therapy, the prevalence of CKD continues to increase in HIV-positive individuals. Recent studies have highlighted the role of apoptosis signal-regulating kinase 1 (ASK1) in driving kidney disease progression through the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase and selective ASK-1 inhibitor GS-444217 was recently shown to reduce kidney injury and disease progression in various experimental models. Therefore we examined the efficacy of ASK1 antagonism by GS-444217 in the attenuation of HIVAN in Tg26 mice. GS-444217-supplemented rodent chow was administered in Tg26 mice at 4 weeks of age when mild GS and proteinuria were already established. After 6 weeks of treatment, the kidney function assessment and histological analyses were performed and compared between age- and gender-matched control Tg26 and GS-444217-treated Tg26 mice. GS-444217 attenuated the development of GS, podocyte loss, tubular injury, interstitial inflammation and renal fibrosis in Tg26 mice. These improvements were accompanied by a marked reduction in albuminuria and improved renal function. Taken together, GS-4442217 attenuated the full spectrum of HIVAN pathology in Tg26 mice. ASK1 signaling cascade is central to the development of HIVAN in Tg26 mice. Our results suggest that the select inhibition of ASK1 could be a potential adjunctive therapy for the treatment of HIVAN.

Deficiency of the Angiotensinase Aminopeptidase A Increases Susceptibility to Glomerular Injury.

Aminopeptidase A (APA) is expressed in glomerular podocytes and tubular epithelia and metabolizes angiotensin II (AngII), a peptide known to promote glomerulosclerosis. In this study, we tested whether APA expression changes in response to progressive nephron loss or whether APA exerts a protective role against glomerular damage and during AngII-mediated hypertensive kidney injury. At advanced stages of FSGS, fawn-hooded hypertensive rat kidneys exhibited distinctly increased APA staining in areas of intact glomerular capillary loops. Moreover, BALB/c APA-knockout (KO) mice injected with a nephrotoxic serum showed persistent glomerular hyalinosis and albuminuria 96 hours after injection, whereas wild-type controls achieved virtually full recovery. We then tested the effect of 4-week infusion of AngII (400 ng/kg per minute) in APA-KO and wild-type mice. Although we observed no significant difference in achieved systolic BP, AngII-treated APA-KO mice developed a significant rise in albuminuria not observed in AngII-treated wild-type mice along with increased segmental and global sclerosis and/or collapse of juxtamedullary glomeruli, microcystic tubular dilation, and tubulointerstitial fibrosis. In parallel, AngII treatment significantly increased the kidney AngII content and attenuated the expression of podocyte nephrin in APA-KO mice but not in wild-type controls. These data show that deficiency of APA increases susceptibility to glomerular injury in BALB/c mice. The augmented AngII-mediated kidney injury observed in association with increased intrarenal AngII accumulation in the absence of APA suggests a protective metabolizing role of APA in AngII-mediated glomerular diseases.

Histopathologic findings associated with APOL1 risk variants in chronic kidney disease

The effects of nephropathy risk variants in the apolipoprotein L1 gene (APOL1) on renal histopathology in African Americans with arterionephrosclerosis or putative ‘hypertension-associated' nephropathy are unknown. APOL1 genotype–phenotype correlations were performed in a blinded manner from renal biopsies in 196 self-reported African Americans with arterionephrosclerosis on kidney biopsy at a large national nephropathology practice. Subjects had chronic kidney disease without nephrotic syndrome. A discovery analysis compared histopathologic changes in the glomerular and tubulointerstitial compartments in 58 subjects with 2 versus 56 subjects with 0 APOL1 risk variants. Validation was performed in biopsies from 82 additional subjects with 0, 1, and 2 risk variants. Two risk variant versus zero risk variant group genotype associations and subphenotypes were assessed by χ2 analyses. ANOVA compared means of continuous variables. In discovery analyses, significantly less obsolescent glomerulosclerosis, more (solidified and disappearing) glomerulosclerosis, more thyroidization-type tubular atrophy, and more microcystic tubular dilatation were seen in patients with two versus zero APOL1 risk alleles. Greater degrees of arteriosclerosis were present in those with zero risk alleles. Segmental glomerulosclerosis did not differ significantly between groups. Presence of two of the following discriminatory histopathologic findings from discovery, that is, <50% obsolescent glomerulosclerosis, thyroidization-type tubular atrophy, and microcystic tubular dilatation, was specific for the presence of two APOL1 risk alleles in the validation phase. African Americans with arterionephrosclerosis who possess two APOL1 risk variants more often lack obsolescent glomerulosclerosis and have greater degrees of (solidified and disappearing) glomerulosclerosis, thyroidization-type tubular atrophy, and microcystic tubular dilation than patients with fewer than two risk variants. These findings support involvement of multiple cell types in subnephrotic forms of APOL1-associated nephropathy, particularly renal tubule cells with resultant tubulointerstitial disease.

IN-DEPTH REVIEW OF HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED NEPHROPATHY

Human Immunodeficiency Virus (HIV)-Associated Nephropathy (HIVAN) is one of the most important renal complications found in HIV-infected individua ls. Morbidity and mortality in this group of patien ts increases due to End-Stage Renal Disease (ESRD). Classic histological characteristics of HIVAN are collapsing Focal Segmental Glomerulosclerosis (FSGS), microcystic tubular dilation and interstitial inflammation and fibrosis. High prevalence of HIVAN among people of African descent can be explained by host genetic susceptibility, which is associated with several genes on human chromosome 22. HIV can infect renal epithelial cells via uncon ventional mechanisms and cause changes in multiple host cellular pathways, especially in renal tubular cells and podocytes. Accurate diagnosis of HIVAN relies mainly on renal biopsy. Antiretroviral thera py is the mainstay treatment for HIVAN and current standard guidelines recommend the initiation of Hig hly Active Antiretroviral Therapy (HAART) in all HIV-infected individuals with HIVAN, regardless of CD4 level. Other possible treatments for HIVAN including steroids, Angiotensin Converting Enzyme ( ACE) inhibitors, renal replacement therapy and renal transplantation are reviewed in this chapter.

HIV-associated nephropathy: a diagnosis in evolution

HIV-1 associated nephropathy (HIVAN) is a clinical and renal histological disease characterized by the presence of heavy proteinuria associated with focal segmental glomerulosclerosis and microcystic tubular dilatation. These renal lesions lead to renal enlargement and rapid progression to kidney failure. People from African ancestry show a unique susceptibility to develop HIVAN. The study by Wearne and colleagues, which includes the largest group of patients of African ancestry with HIVAN studied so far, describes a novel renal histological variant of HIVAN, and suggests that antiretroviral therapies improve the clinical outcome of all HIV-associated renal diseases. These findings, when interpreted in the context of recent advances in our understanding of the molecular pathogenesis and genetics of HIVAN, will facilitate the recognition of all clinical variants of HIVAN as well the planning of better screening, prevention, and treatment programs for all HIV nephropathies.

Advances in Our Understanding of the Pathogenesis of HIV-1 Associated Nephropathy in Children

Childhood HIV-1 associated nephropathy (HIVAN) is a clinical and renal histological disease characterized by heavy proteinuria associated with focal and segmental glomerular sclerosis and/or mesangial hyperplasia in combination with microcystic tubular dilatation. These lesions lead to renal enlargement and rapid progression to kidney failure. Children of African ancestry have a unique susceptibility to developing HIVAN. It is estimated that approximately 300,000 HIV-infected children living in the sub-Saharan Africa could develop HIVAN if they do not receive appropriate antiretroviral therapy. This article discusses recent developments and controversies related to the pathogenesis of childhood HIVAN. The role of host genetic factors, including the newly identified variants in the APOL1 gene, is discussed in the context of previous studies that established the pathological paradigm for HIVAN, and our current understanding of the functional genomics analysis. Hopefully, these advances will provide new research opportunities to generate better treatments for children with HIVAN.

HIV-associated nephropathy: pathogenesis

HIV-associated nephropathy (HIVAN) is characterized histologically by a collapsing form of focal segmental glomerulosclerosis (FSGS), microcystic tubular dilation, interstitial inflammation and fibrosis. In this review, we provide a summary of the current state of knowledge about the mechanisms involved in the pathogenesis of HIVAN. Two variants in the ApoL1 gene have been identified as the susceptibility alleles that account for a majority of the increased risk of FSGS and nondiabetic end-stage renal disease in blacks. HIVAN1 and HIVAN2 are the other host susceptibility genes that have been identified in animal models for HIVAN. HIV infects renal tubular epithelial cells likely through direct cell-cell transmission. Both in-vivo and in-vitro evidence suggests that Nef and Vpr are the key viral genes mediating HIVAN. Nef induces podocyte dysfunction, whereas Vpr induces renal tubular epithelial cell apoptosis. HIVAN results from direct infection by HIV-1 and expression of viral genes, especially Nef and Vpr, in renal epithelial cells in a genetically susceptible host. The infected renal epithelium acts as a separate viral compartment from the blood and facilitates evolution of strains distant from blood. Dysregulation of several host cellular pathways, including those involved in cell cycle and apoptosis, ultimately results in the unique histopathological syndrome of HIVAN.

HIV-Associated Nephropathy: Clinical Presentation, Pathology, and Epidemiology in the Era of Antiretroviral Therapy

The classic kidney disease of human immunodeficiency virus (HIV) infection, HIV-associated nephropathy, is characterized by progressive acute renal failure, often accompanied by proteinuria and ultrasound findings of enlarged, echogenic kidneys. Definitive diagnosis requires kidney biopsy, which shows collapsing focal segmental glomerulosclerosis with associated microcystic tubular dilatation and interstitial inflammation. Podocyte proliferation is a hallmark of HIV-associated nephropathy, although this classic pathology is observed less frequently in antiretroviral-treated patients. The pathogenesis of HIV-associated nephropathy involves direct HIV infection of renal epithelial cells, and the widespread introduction of combination antiretroviral therapy has had a significant impact on the natural history and epidemiology of this unique disease. These observations have established antiretroviral therapy as the cornerstone of treatment for HIV-associated nephropathy in the absence of prospective clinical trials. Adjunctive therapy for HIV-associated nephropathy includes angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, as well as corticosteroids in selected patients with significant interstitial inflammation or rapid progression.

Response of HIV-associated proteinuria to antiretroviral therapy in HIV-1-infected children

HIV-associated nephropathy has been found in children with HIV-1 infection as a late manifestation of this disease; it is associated with nephrotic syndrome with focal segmental glomerulosclerosis and/or mesangial hyperplasia with microcystic tubular dilatation. This is quite rare in children and no cases have been reported from India. Several mechanisms have been hypothesized for the HIV-induced renal damage. We report on two HIV-infected children with HIV-associated proteinuria and dramatic response to antiretroviral therapy.

Animal models of HIV-associated nephropathy

HIV-1-associated nephropathy is characterized clinically by proteinuria with azotemia and pathologically by collapsing focal segmental glomerulosclerosis with tubulointerstitial nephritis and microcystic tubular dilatation. This review summarizes the manner in which different transgenic animal models contribute to our knowledge of the pathogenesis of HIV-1-associated nephropathy. The most widely studied has been a transgenic mouse model bearing a gag and pol-deleted proviral construct that develops renal disease with many of the clinical and pathologic characteristics seen in HIV-1-associated nephropathy. Studies using this model have helped to highlight the role of HIV-1 viral gene expression in renal cells, podocyte dysregulation, and genetic host factors in the pathogenesis of HIV-1-associated nephropathy. This model has provided the key insights that led to detection of HIV-1 in human kidney epithelial cells. Other transgenic models have helped define critical roles for individual HIV gene products (Nef and Vpr) in the pathogenesis of HIV-1-associated nephropathy. Transgenic mouse models have also provided a method to discover new treatments targeting various steps in the pathogenesis of this disease. Transgenic animal models of HIV-1-associated nephropathy have contributed greatly to the progress made toward understanding the pathogenesis of this disease.

Role of fibroblast growth factor-binding protein in the pathogenesis of HIV-associated hemolytic uremic syndrome

A characteristic finding of childhood HIV-associated hemolytic uremic syndrome (HIV-HUS) is the presence of endothelial injury and microcystic tubular dilation, leading to a rapid progression of the renal disease. We have previously shown that a secreted fibroblast growth factor-binding protein (FGF-BP) is upregulated in kidneys from children affected with HIV-HUS and HIV nephropathy. Here, we sought to determine the potential role of FGF-BP in the pathogenesis of HIV-HUS. By immunohistochemical and in situ hybridization studies, we observed FGF-BP protein and mRNA upregulation in regenerating renal tubular epithelial cells from kidneys of HIV-Tg26 mice with late-stage renal disease, that is, associated with the development of microcystic tubular dilatation and accumulation of FGF-2. Moreover, FGF-BP increased the FGF-2-dependent growth and survival of cultured primary human renal glomerular endothelial cells and enhanced FGF-2-induced MAPK/ERK2 activation, as well as the proliferation of immortalized GM7373 endothelial cells. We propose that HIV-Tg26 mice are a clinically relevant model system to study the role of FGF-BP in the pathogenesis of HIV-associated renal diseases. Furthermore, the upregulation of FGF-BP by regenerating renal tubular epithelial cells may provide a mechanism by which the regenerative and angiogenic activity of FGF-2 in renal capillaries can be modulated in children with HIV-HUS and other renal disease.

Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy

Human immunodeficiency virus (HIV)-1-associated nephropathy (HIVAN) is characterized by collapsing focal and segmental glomerulosclerosis (FSGS) and microcystic tubular dilatation. HIV-1 infection is also associated with other forms of nephropathy, including mesangial hyperplasia. Since HIV-1 gene products are detected in podocytes and other renal cells, it remains uncertain whether podocyte-restricted HIV-1 gene expression can account for the full spectrum of renal lesions involving nonpodocytes. To define the role of podocyte-restricted HIV-1 gene expression in the progression of HIVAN, we generated transgenic mice that express nonstructural HIV-1 genes selectively in podocytes. Four of the seven founder mice developed proteinuria and nephropathy. In a subsequently established transgenic line, reverse transcription-polymerase chain reaction (RT-PCR) analysis detected mRNAs for vif, vpr, nef, and spliced forms of tat and rev, but not vpu, in the kidney. In situ hybridization localized HIV-1 RNA to the podocyte. Transgenic mice on FVB/N genetic background exhibited cuboidal morphology of podocytes with reduced extension of primary and foot processes at 2 weeks of age. After 3 weeks of age, these mice developed massive and nonselective proteinuria with damage of podocytes and other glomerular cells and, after 4 weeks of age, collapsing FSGS and microcystic tubular dilatation. In marked contrast, transgenic mice with C57BL/6 genetic background showed either normal renal histology or only mild mesangial expansion without overt podocyte damage. The present study demonstrates that podocyte-restricted expression of HIV-1 gene products is sufficient for the development of collapsing glomerulosclerosis in the setting of susceptible genetic background.

A 20-year history of childhood HIV-associated nephropathy.

In 1984, physicians in New York and Miami reported HIV-infected adult patients with heavy proteinuria and rapid progression to end-stage renal disease. These patients showed large edematous kidneys with a combination of focal segmental glomerulosclerosis (FSGS) and tubulointerstitial lesions. This renal syndrome, named HIV-associated nephropathy (HIVAN), was found predominantly in African Americans. Subsequent studies confirmed the presence of HIVAN in children, who frequently develop nephrotic syndrome in association with FSGS and/or mesangial hyperplasia with microcystic tubular dilatation. Since then, substantial progress has been made in our understanding of the etiology and pathogenesis of HIVAN. This article reviews 20 years of research into the pathogenesis of HIVAN and discusses how these concepts could be applied to the treatment of children with HIVAN. HIV-1 infection plays a direct role in the pathogenesis of childhood HIVAN, at least partially by affecting the growth and differentiation of glomerular and tubular epithelial cells and enhancing the renal recruitment of infiltrating mononuclear cells and cytokines. An up-regulation of renal heparan sulfate proteoglycans seems to play a relevant role in this process, by increasing the recruitment of heparin-binding growth factors (i.e., FGF-2), chemokines, HIV-infected cells, and viral proteins (i.e., gp120, Tat). These changes enhance the infectivity of HIV-1 in the kidney and induce injury and proliferation of intrinsic renal cells. Highly active anti-retroviral therapy (HAART) appears to be the most promising treatment to prevent the progression of childhood HIVAN. Hopefully, in the near future, better education, prevention, and treatment programs will lead to the eradication of this fatal childhood disease.

A novel HIV-1 transgenic rat model of childhood HIV-1–associated nephropathy

A characteristic finding of human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is the presence of heavy proteinuria, focal or global glomerulosclerosis, and microcystic tubular dilatation leading to renal enlargement, and rapid progression to end-stage renal disease (ESRD). We have recently developed the first HIV-1 transgenic rat model that carry a noninfectious HIV-1 DNA construct lacking 3.1 kb of sequence overlapping the gag and pol sequences, and develop many of the clinical lesions seen in HIV-infected patients, including HIVAN. To gain further insight into the pathogenesis of childhood HIVAN, we followed the clinical and renal pathologic outcome of 165 HIV-1 transgenic (HIV-Tg) rats and their respective control littermates for a period of 18 months. HIV-1 Tg rats progressively developed proteinuria and renal histologic lesions similar to those seen in children with HIVAN, leading to chronic renal failure. By in situ hybridization, HIV-1 genes were detected in glomerular and tubular epithelial cells and infiltrating mononuclear cells, which also expressed the HIV-1 envelop protein gp120. The development of HIVAN was associated with the accumulation of basic fibroblast growth factor (bFGF) in the kidney. These data support the notion that HIV-1 plays a direct role in the pathogenesis of HIVAN, by affecting the function and growth of renal epithelial cells, inducing the recruitment of mononuclear cells, and accumulating bFGF in the kidney, even in the absence of viral replication. These rats may provide an excellent model system to study the pathogenesis of childhood HIVAN.

Glomerulosclerosis and viral gene expression in HIV-transgenic mice: Role of nef

Human immunodeficiency virus (HIV)-associated nephropathy is characterized by focal segmental glomerulosclerosis and microcystic tubular dilation. We have previously described a mouse transgenic for a Deltagag-pol HIV-1 genome, which develops glomerulosclerosis, cutaneous papillomas, and cataracts. We developed mice transgenic for a Deltagag-pol-nef HIV genome in order to investigate the role of the nef gene in these phenotypes. One transgenic line, X5, expressed HIV mRNA in kidney and consistently manifested focal segmental glomerulosclerosis and tubular dilation by six weeks of age. Northern analysis indicated that renal transgene expression was higher in the Deltagag-pol-nef mice compared with the Deltagag-pol mice. In situ hybridization and immunostaining demonstrated HIV RNA and protein expression within the glomerular epithelial cells and tubular epithelial cells. These cell types showed histologic evidence of toxicity, including vacuolation and detachment from basement membrane, and exhibited increased rates of apoptosis. These data suggest that the renal disease seen in the Deltagag-pol-nef transgenic mouse may be caused by the expression of HIV genes within renal epithelial cells, that this expression may induce cellular toxicity, including apoptosis, and that nef is not required for the induction of renal disease. We have previously described mice bearing the nef gene, which do not manifest renal disease. In further experiments, Deltagag-pol-nef mice were bred with nef mice; these dual-transgenic mice developed renal disease that generally resembled that seen in Deltagag-pol-nef mice, but with somewhat more severe glomerulosclerosis and less severe tubulointerstitial injury. The results of these transgenic studies suggest that the role of nef is complex and may act both to reduce transgene expression and to potentiate glomerular injury induced by other HIV-1 gene products.

The role of PAX2 in normal and abnormal development of the urinary tract.

The molecular etiology of many urinary tract abnormalities in children remains unknown, but a number of genes with a key role in urogenital development have now been identified. PAX2, one such gene, encodes a transcription factor which is critically required for epithelial differentiation within the urogenital tract. Recent studies suggest that PAX2 mutations lead to urological abnormalities and renal failure, while overexpression of PAX2 in the kidneys of mice causes multifocal microcystic tubular dilatation. In humans persistent PAX2 expression has been identified in multicystic dysplastic kidneys. In this review, recent research on the developmental gene, PAX2, and its involvement in normal and abnormal kidney development is summarized. In addition, an overview of the phenotypes associated with either loss-of-function PAX2 mutations or PAX2 overexpression is presented. A brief summary of factors that are known to regulate PAX2 and genes that may be regulated by PAX2 protein is also included.

HIV-1-associated nephropathy and response to highly-active antiretroviral therapy

A 37-year-old African-American man with schizophrenia and bipolar disorder was admitted with psychotic symptoms after stopping his medications. Within 2 weeks of admission, his blood urea increased from 8 to 21 mmol/L and creatinine from 203 to 450 mol/L. 3 weeks later his serum sodium was 135 mmol/L, potassium 6·7 mmol/L, chloride 109 mmol/L, bicarbonate 13 mmol/L, urea 32 mmol/L, and creatinine 770 mol/L. Calculated creatinine clearance was 7 mL/min and he required haemodialysis. His blood pressure was 132/70 mm Hg, weight 77 kg, and height 162 cm. He had pharyngeal thrush, penile warts, and prominent jugular veins without peripheral oedema. His medications were olanzapine, haloperidol, sodium valproate, and lorazepam. Additional laboratory tests indicated a normal urinary sediment on microscopy, urinary protein 9·9 g/day with normal urine and serum immunoelectrophoresis. He had a mild normocytic, normochromic anaemia, with haemoglobin of 95 g/L, and a normal platelet count. Serum albumin was 14 g/L and total cholesterol 7·2 mmol/L. Tests for collagen diseases, vasculitic syndromes, or infection with hepatitis or herpes group viruses were negative, and complement levels were normal; these tests were repeated 6 weeks later and remained unchanged. HIV-1 antibodies were present on enzyme-linked immunosorbent assay and western blot. His CD4 lymphocyte count was 0·04 10/L and the CD8 count 0·42 10/L. Serum HIV-1 RNA by branched chain DNA assay was 906 000 copies per mL. An ultrasound examination was remarkable for 13·5 cm kidneys with increased echogenicity. A percutaneous kidney biopsy was done a week before the initiation of dialysis and showed changes typical of HIV-1associated nephropathy. On light microscopy a core of renal cortex had fourteen glomeruli, of which one glomerulus was globally sclerotic. The other glomeruli were normocellular but had significant tuft collapse, with more than 70% having epithelial pseudocrescents. The interstitium showed prominent microcystic tubular dilatation containing proteinaceous casts (figure, A). The vessels were unremarkable, and glomerular immunofluorescence staining was negative. Electron microscopy confirmed collapsing glomerulopathy without endocapillary hypercellularity, plus marked hypertrophy and hyperplasia of the podocytes leading to epithelial pseudocrescents. Endothelial cells contained tubuloreticular cytoplasmic inclusions. Triple antiretroviral therapy with stavudine 20 mg/day, lamivudine 50 mg/day, and nelfinavir 1250 mg twice daily was started 1 week before haemodialysis. After13 weeks of treatment and 12 weeks of haemodialysis three times per week, a 24-hour urine collection (3·5 L) contained 0·7 g protein and 10·6 mmol creatinine. 2 weeks later repeat 24hour urine tests were similar and dialysis was discontinued. A repeat percutaneous renal biopsy at that time showed 18

Immunopathological characteristics of in situ T-cell subpopulations in human immunodeficiency virus-associated nephropathy

Human immunodeficiency virus—associated nephropathy (HIVAN) is a common form of nephropathy present in HIV-infected individuals that clinically presents with proteinuria that is frequently in the nephrotic range, less often with hematuria, and with a course that may evolve to irreversible azotemia ultimately resulting in renal failure. Pediatric and adult HIV-positive patients both experience HIVAN morphologically after displaying focal segmental glomerulosclerosis, diffuse mesangial hyperplasia, microcystic tubular dilatation, interstitial inflammation, edema, and fibrosis. There is minimal information regarding the interstitial inflammatory cell infiltrate, despite the possibility that these cells may play an important role in the etiology of HIVAN. This study was designed to characterize and compare several morphological and immunopathological features of clearly established HIVAN, particularly the hematopoietic cell markers present on the interstitial inflammatory cells and the state of Tlymphocyte activation (ie, class II expression). Quantitative grading of HIVAN kidneys showed that CD4-positive and CD8-positive T cells comprised the major cell populations in the interstitium, often with CD4-positive T cells exceeding or being equivalent in number to CD8-positive T cells. B cells and macrophages were negligible components of the infiltrate. Human leukocyte antigen-DR class II molecules were found to be increased on the interstitial T cells as well as on all glomerular cells and endothelial cells. There was no significant relationship established between the immunophenotype of the interstitial inflammatory cells and other morphological, ultrastructural, immunofluorescent, or clinical features. These data imply that the inflammatory infiltrate in HIVAN is largely composed of activated T cells. At this point the role of these interstitial T cells in HIVAN is undetermined, although it can be speculated that they may be participating as antiviral or autoreactive immune effector cells imparting renal injury in this entity.

Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes.

Patients infected with human immunodeficiency virus type 1 (HIV-1) develop a renal syndrome characterized by proteinuria, renal failure, and focal segmental glomerulosclerosis. By using a noninfectious HIV-1 DNA construct lacking the gag and pol genes, three transgenic mouse lines have been generated that develop a syndrome remarkably similar to the human disease. In the present study, we have characterized in detail one of these lines, Tg26. In Tg26 mice, proteinuria was detectable at approximately 24 days of age, followed by severe nephrotic syndrome and rapid progression to end-stage renal failure. Renal histology showed focal segmental glomerulosclerosis and microcystic tubular dilatation. Indirect immunofluorescence studies demonstrated increased accumulation of the basement membrane components laminin, collagen type IV, and heparan sulfate proteoglycan. The viral protein Rev was present in sclerotic glomeruli. Northern blot analysis of total renal RNA showed expression of viral genes prior to the appearance of histologic renal disease, with greatly diminished viral gene expression late in the disease course. Kidneys from transgenic mice expressed increased steady-state levels of collagen alpha 1(IV) mRNA when glomerulosclerosis was present. We conclude that the presence of HIV-1 genes is associated with progressive renal dysfunction and glomerulosclerosis in transgenic mice.