HIV-associated nephropathy is a late, not early, manifestation of HIV-1 infection.
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BACKGROUND: Human immunodeficiency virus-associated nephropathy (HIVAN) can be the initial presentation of HIV-1 infection. As a result, many have assumed that HIVAN can occur at any point in the infection. This issue has important implications for appropriate therapy and, perhaps, for pathogenesis. Since the development of new case definitions for acquired immunodeficiency syndrome (AIDS) and better tools to assess infection, the relationship of HIVAN to the time of AIDS infection has not been addressed. In this study, we reassessed the stage of infection at the time of HIVAN diagnosis in 10 patients, and we reviewed all previously published cases applying the new case definitions to assess stage of infection. METHODS: HIVAN was confirmed by kidney biopsy in HIV seropositive patients with azotemia and/or proteinuria. CD4+ cell count and plasma HIV-1 RNA copy number were measured. We also reviewed all published cases of HIVAN to determine if AIDS-defining conditions, by current Centers for Disease Control definitions, were present in patients with biopsy-proven HIVAN. RESULTS: Twenty HIV-1 seropositive patients with proteinuria and an elevated creatinine concentration were biopsied. HIVAN was the single most common cause of renal disease. CD4+ cell count was below 200/mm3 in all patients with HIVAN, fulfilling Centers for Disease Control criteria for an AIDS-defining condition. HIV-1 plasma RNA was detectable in all patients with HIVAN. In reviewing previous reports, an AIDS-defining condition was present in virtually all patients with HIVAN. CONCLUSION: HIVAN develops late, not early, in the course of HIV-1 infection following the development of AIDS. This likely accounts for the poor prognosis noted in previous publications and has implications for pathogenesis. In addition, given the detectable viral RNA levels, highly active antiretroviral therapy is indicated in HIVAN. Highly active antiretroviral therapy may improve survival as well as alter the natural history of HIVAN. (+info)
Up-regulation of Duffy antigen receptor expression in children with renal disease.
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BACKGROUND: The Duffy antigen chemokine receptor (DARC) is a promiscuous chemokine receptor that binds chemokines from the C-X-C and C-C families. DARC was initially described on red blood cells, but subsequent studies have demonstrated DARC protein expression on renal endothelial and epithelial cells, even in Duffy-negative individuals whose red cells lack DARC. Because approximately 68% of African Americans lack the Duffy/DARC on their red cells, we carried out experiments to identify the specific renal cells expressing DARC protein and mRNA in African American children and to define whether DARC expression was altered in renal inflammatory processes. METHODS: Immunohistochemistry and in situ hybridization studies were done in 28 renal sections from children with each of the following diagnoses: HIV nephropathy (HIVAN), HIV-associated hemolytic uremic syndrome (HIV-HUS), HIV infection without renal disease, HIV-negative children without renal disease, and Argentinean children with classic HUS. RESULTS: The predominant localization of DARC mRNA and protein was found in endothelial cells underlying postcapillary renal venules in all patients studied. However, DARC mRNA and protein were significantly up-regulated in peritubular and glomerular capillaries, collecting duct epithelial cells, and interstitial inflammatory cells in children with HIVAN, HIV-HUS, and classic HUS. CONCLUSION: These findings support the notion that the renal DARC is linked to the inflammatory cascade and that African American children may be at risk of accumulating chemokines in renal tissues. (+info)
Hepatitis C virus-associated glomerular disease in patients with human immunodeficiency virus coinfection.
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Chronic infection with hepatitis C virus (HCV) has been linked to the development of glomerular disease. HCV infection is highly prevalent among intravenous drug users, a population that is also at risk for HIV coinfection. This study reports the clinical-pathologic features and outcome of HCV-associated glomerular disease (HCV-GD) in 14 patients with HIV coinfection. All were intravenous drug users and all but one were African-Americans. Renal presentations included renal insufficiency, microscopic hematuria with active urine sediment, hypertension, and nephrotic syndrome or nephrotic-range proteinuria without hypercholesterolemia. Hypocomplementemia and cryoglobulinemia were present in 46 and 33% of patients, respectively. The predominant renal biopsy findings were membranoproliferative glomerulonephritis type 1 or type 3 (Burkholder subtype) in 79% of patients and membranous glomerulopathy with atypical features in 21% (including overlap with collapsing glomerulopathy in one patient). The clinical course was characterized by rapid progression to renal failure requiring dialysis. The overall morbidity and mortality were high with median time of 5.8 mo to dialysis or death. Although most patients died in renal failure, cause of death was primarily attributable to long-term immunosuppression and advanced AIDS. Patients with AIDS had shorter survival than those without (median survival time of 6.1 mo versus 45.9 mo, log-rank test P = 0.02). Only two patients were alive with stable renal function at follow-up of 28.5 mo. In patients with HCV-GD, coinfection with HIV leads to an aggressive form of renal disease that can be easily confused with HIV-associated nephropathy. Although hypocomplementemia, cryoglobulinemia, and more prominent hypertension and microscopic hematuria may provide clues to the presence of HCV-GD, renal biopsy is essential to differentiate HCV-GD from HIV-associated nephropathy. (+info)
Renal lesions in AIDS: a biopsy and autopsy study.
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We studied renal lesions at biopsy (20 cases) and at autopsy (21 cases) among patients with the acquired immune deficiency syndrome (AIDS). Nephrotic syndrome with concomitant renal insufficiency was most common indication for biopsy. 85 percent of biopsies showed features of HIV associated nephropathy (HIVAN) which include: Focal segmental glomerulosclerosis (FSGS), glomerular collapse and mesangial hyperplasia. These glomerular changes were always accompanied by tubular microcysts and ultrastructurally, tubuloreticular inclusions (TRI) within the glomerular endothelium were often noted. Changes of HIVAN were also seen in two cases who were HIV negative at the time of biopsy but were positive on repeat testing. Minimal change disease, mesangiocapillary glomerulonephritis and diffuse proliferative lupus nephritis were other biopsy lesions. Autopsy findings were HIVAN (33 percent), tubular necrosis and opportunistic infections. We conclude that HIVAN is a distinct clinicopathologic entity that may sometimes be the first manifestation of the underlying disease state. (+info)
Renal lesions associated with AIDS--an autopsy study.
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Kidneys from 55 cases (20 with HIV infection and 35 with AIDS) were studied by routine Haematoxylin and Eosin stains and special stains (PAS, PASM GMS, ZN, Mucicarmine and Congo red) to evaluate, glomerular, interstitial and vascular pathology. Twenty-four of the 35 (68.6%) cases of AIDS showed infective aetiology which included 17 cases (48.5%) of tuberculosis, 5 cases (14.4%) of fungal infection (3 cryptococcus neoformans and 2 candida species) and 2 cases (5.7%) of CMV infection. Other lesions noted were amyloidosis and tubular calcinosis. HIV associated nephropathy (HIVAN) was not detected in any of the cases. Intravenous drug abuse was not a risk factor in our cases which probably explains the absence of HIV associated nephropathy in the present study. (+info)
Chemokine receptor CCR5 and CXCR4 expression in HIV-associated kidney disease.
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The chemokine receptors CCR5 and CXCR4 have been identified as essential coreceptors for entry of HIV-1 strains into susceptible cells. Direct infection of renal parenchymal cells has been implicated in the pathogenesis of HIV-associated renal disease, although data are conflicting. The localization of CCR5 and CXCR4 in kidneys with HIV-associated renal disease is unknown. Formalin-fixed, paraffin-embedded renal biopsies from patients with HIV-associated nephropathy (HIVAN) (n = 13), HIV-associated immune complex glomerulonephritis (n = 3), HIV-associated thrombotic microangiopathy (n = 1), and HIV-negative patients with collapsing glomerulopathy (n = 8) were analyzed in this study. Cellular sites of expression of CCR5 and CXCR4 were identified by immunohistochemistry and by in situ hybridization. The presence of HIV-1 was detected by immunohistochemistry and by in situ hybridization. Expression of both chemokine receptors CCR5 and CXCR4 was undetectable in intrinsic glomerular, tubular, and renovascular cells in all analyzed cases. In the presence of tubulointerstitial inflammation, CCR5 and CXCR4 expression was localized to infiltrating mononuclear leukocytes. HIV-1 protein was undetectable by immunohistochemistry in all cases of HIV-associated renal disease. HIV-1 RNA was identified in one case of HIVAN but was restricted to infiltrating leukocytes. HIV-1 RNA was not detected in intrinsic renal cells in all analyzed cases. Identifying the cellular expression of HIV-coreceptors CCR5 and CXCR4 may help to clarify which tissues are permissive for direct HIV infection. These data do not support a role of productive HIV-1 infection of renal parenchymal cells in the pathogenesis of HIV-associated renal disease. (+info)
Diuretic MAG3 scintirenography in children with HIV nephropathy: diffuse parenchymal dysfunction.
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HIV nephropathy (HIVN) is prevalent in 15%-56% of HIV-infected children and induces mild to severe progressive nephropathy. METHODS: A total of 33 renal diuretic scintirenographic studies with 99mTc-mercaptoacetyltriglycine (MAG3) were reviewed and analyzed from 23 HIV pediatric patients, 21 of whom had HIVN with varying degrees of renal impairment. Results were compared with 10 studies of control patients of matching ages. Visual interpretation of images and renograms as well as semiquantitative analyses were performed. Variables compared were size of kidneys, time of peak and one-half peak activities, residual (or retained) cortical activity at 20 min, ratio of cortical activity at 2.5-20 min, and ratio of kidney activity to kidney plus background activity at 2 min. The results of MAG3 renal studies were also compared with laboratory data pertaining to creatinine clearance in all patients and with sonography in 17 patients. RESULTS: In most patients with HIVN (18/21), the kidneys were larger than normal, with a diffuse parenchymal dysfunction (decreased uptake, slow processing, and increased retention of activity) and flat renograms, findings similar to those observed in other diffuse parenchymal diseases. In all patients with HIVN, semiquantitative analysis (paired t test) showed statistically significant differences from control patients for all variables. On ANOVA, a statistically significant correlation was found between most scintigraphic parameters and the severity of renal impairment. Of the 17 concurrent sonographic studies in HIVN patients, 7 showed no abnormalities, whereas the results of scintigraphy were abnormal. CONCLUSION: Diuretic MAG3 scintirenography shows nonspecific diffuse parenchymal dysfunction in pediatric patients with HIVN. Such dysfunction may provide corroborative evidence of HIVN and should be recognized when the test is performed for standard indications. Further work is necessary to prove that the test has indeed the high sensitivity and good correlation with the seventy of HIVN suggested in this population; the test may be useful to follow up the progression of disease and the effect of treatment. (+info)
Podocyte cell cycle regulation and proliferation in collapsing glomerulopathies.
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BACKGROUND: Mature podocytes are growth-arrested because of the expression of cyclin-dependent kinase inhibitors. Under pathological conditions, podocytes may undergo mitosis, but not cell division. Exceptions to this rule are collapsing glomerulopathies (CGs), including HIV-associated nephropathy (HIVAN) and idiopathic CG, where podocytes undergo a dysregulation of their differentiated phenotype and proliferate. METHODS: To shed light on the mechanism underlying podocyte proliferation in CG, we analyzed the expression of the proliferation marker Ki-67, cyclins (A, D1), cyclin-dependent kinase inhibitors (p27, p57), and podocyte differentiation marker synaptopodin in eight cases of HIVAN and two cases of idiopathic CG. Normal fetal and adult kidneys served as controls. RESULTS: Both HIVAN and idiopathic CG showed a marked reduction in the expression of p27, p57, and cyclin D1 (absent in 69, 62, and 80% of all glomeruli, respectively). Cyclin A and Ki-67 were expressed in 11 and 29% of all glomeruli. Moreover, there was partial loss of synaptopodin and cyclin D1 expression in nonaffected glomeruli. CONCLUSIONS: The loss of p27 and p57 leading to expression of cyclin A may account for the activation of podocyte proliferation in CG. Furthermore, the loss of cyclin D1 from histologically normal glomeruli suggests a possible role of cyclin D1 in mediating the dysregulation of the podocyte cell cycle in CG. These novel findings offer insight into the molecular regulation of mature podocyte differentiation. Podocyte proliferation in CG provides evidence in support of a previously underestimated plasticity of mature podocytes. (+info)