RESUMEN
The COVID-19 era has been a reminder to clinicians around the world of the important role that viral infections play in promoting glomerular disease. Several viral infections including human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus 2, Epstein-Barr virus, cytomegalovirus, and parvovirus B19 can cause podocyte injury and present with a collapsing glomerulopathy (CG) variant of focal segmental glomerulosclerosis or minimal change disease. CG associated with COVID-19 has been termed COVID-19-associated nephropathy due to its striking resemblance to HIV-associated nephropathy. Host susceptibility is a major determinant of viral infection-associated CG, and the presence of two APOL1 risk variants explains most of the racial predilection to viral-associated CG observed in individuals of African ancestry. Interactions between APOL1 risk variants, viral genes, and the systemic inflammatory response to viral infection all contribute to kidney injury. This review will summarize our current knowledge of viral infection-associated CG, focusing primarily on the clinical presentation, histological features, mechanisms, and disease course of HIV-associated nephropathy and COVID-19-associated nephropathy.
Asunto(s)
COVID-19 , Glomeruloesclerosis Focal y Segmentaria , SARS-CoV-2 , Humanos , COVID-19/patología , COVID-19/complicaciones , COVID-19/virología , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/virología , Glomeruloesclerosis Focal y Segmentaria/etiología , SARS-CoV-2/patogenicidad , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Apolipoproteína L1/genética , Virosis/complicaciones , Virosis/patología , Virosis/virología , Nefrosis Lipoidea/patología , Nefrosis Lipoidea/virología , Nefropatía Asociada a SIDA/patología , Nefropatía Asociada a SIDA/virología , Nefropatía Asociada a SIDA/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/virologíaRESUMEN
HIV disease remains prevalent in the United States and is particularly prevalent in sub-Saharan Africa. Recent investigations revealed that mitochondrial dysfunction in kidney contributes to HIV-associated nephropathy (HIVAN) in Tg26 transgenic mice. We hypothesized that nicotinamide adenine dinucleotide (NAD) deficiency contributes to energetic dysfunction and progressive tubular injury. We investigated metabolomic mechanisms of HIVAN tubulopathy. Tg26 and wild-type (WT) mice were treated with the farnesoid X receptor (FXR) agonist INT-747 or nicotinamide riboside (NR) from 6 to 12 wk of age. Multiomic approaches were used to characterize kidney tissue transcriptomes and metabolomes. Treatment with INT-747 or NR ameliorated kidney tubular injury, as shown by serum creatinine, the tubular injury marker urinary neutrophil-associated lipocalin, and tubular morphometry. Integrated analysis of metabolomic and transcriptomic measurements showed that NAD levels and production were globally downregulated in Tg26 mouse kidneys, especially nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway. Furthermore, NAD-dependent deacetylase sirtuin3 activity and mitochondrial oxidative phosphorylation activity were lower in ex vivo proximal tubules from Tg26 mouse kidneys compared with those of WT mice. Restoration of NAD levels in the kidney improved these abnormalities. These data suggest that NAD deficiency might be a treatable target for HIVAN.NEW & NOTEWORTHY The study describes a novel investigation that identified nicotinamide adenine dinucleotide (NAD) deficiency in a widely used HIV-associated nephropathy (HIVAN) transgenic mouse model. We show that INT-747, a farnesoid X receptor agonist, and nicotinamide riboside (NR), a precursor of nicotinamide, each ameliorated HIVAN tubulopathy. Multiomic analysis of mouse kidneys revealed that NAD deficiency was an upstream metabolomic mechanism contributing to HIVAN tubulopathy.
Asunto(s)
Nefropatía Asociada a SIDA , Ratones Transgénicos , NAD , Niacinamida , Compuestos de Piridinio , Sirtuina 3 , Animales , NAD/metabolismo , Nefropatía Asociada a SIDA/metabolismo , Nefropatía Asociada a SIDA/genética , Nefropatía Asociada a SIDA/patología , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos de Piridinio/farmacología , Sirtuina 3/metabolismo , Sirtuina 3/genética , Sirtuina 3/deficiencia , Modelos Animales de Enfermedad , Nicotinamida Fosforribosiltransferasa/metabolismo , Nicotinamida Fosforribosiltransferasa/genética , Ratones , Mitocondrias/metabolismo , Mitocondrias/patología , Progresión de la Enfermedad , Metabolómica , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/deficiencia , Riñón/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Citocinas/metabolismoRESUMEN
Collapsing focal segmental glomerulosclerosis (FSGS), also known as collapsing glomerulopathy (CG), is the most aggressive variant of FSGS and is characterized by a rapid progression to kidney failure. Understanding CG pathogenesis represents a key step for the development of targeted therapies. Previous work implicated the telomerase protein component TERT in CG pathogenesis, as transgenic TERT expression in adult mice resulted in a CG resembling that seen in human primary CG and HIV-associated nephropathy (HIVAN). Here, we used the telomerase-induced mouse model of CG (i-TERTci mice) to identify mechanisms to inhibit CG pathogenesis. Inactivation of WIP1 phosphatase, a p53 target acting in a negative feedback loop, blocked disease initiation in i-TERTci mice. Repression of disease initiation upon WIP1 deficiency was associated with senescence enhancement and required transforming growth factor-ß functions. The efficacy of a pharmacologic treatment to reduce disease severity in both i-TERTci mice and in a mouse model of HIVAN (Tg26 mice) was then assessed. Pharmacologic inhibition of WIP1 enzymatic activity in either the telomerase mice with CG or in the Tg26 mice promoted partial remission of proteinuria and ameliorated kidney histopathologic features. Histological as well as high-throughput sequencing methods further showed that selective inhibition of WIP1 does not promote kidney fibrosis or inflammation. Thus, our findings suggest that targeting WIP1 may be an effective therapeutic strategy for patients with CG.
Asunto(s)
Nefropatía Asociada a SIDA , Glomeruloesclerosis Focal y Segmentaria , Insuficiencia Renal , Telomerasa , Adulto , Humanos , Ratones , Animales , Glomeruloesclerosis Focal y Segmentaria/patología , Telomerasa/uso terapéutico , Nefropatía Asociada a SIDA/patología , Proteinuria , Insuficiencia Renal/complicaciones , Modelos Animales de EnfermedadRESUMEN
Although antiretroviral therapy (ART) has increased life expectancy in people with HIV-1 (PWH), acute and chronic kidney disease remain common in this population and are associated with poor outcomes. A broad spectrum of kidney disorders can be observed in PWH, some of which are directly related to intrarenal HIV infection and gene expression. HIV-associated nephropathy (HIVAN) was the most common kidney disease in PWH before ART became available. Animal models and human biopsy studies established the causal relationships between direct HIV-1 infection of renal epithelial cells and HIVAN, expression of viral genes in renal epithelial cells, and dysregulation of host genes involved in cell differentiation and cell cycle. In this review, we provide a summary of the body of work demonstrating HIV-1 infection of epithelial cells in the kidney and recent advancements in the understanding of viral entry mechanisms and consequences of HIV-1 gene expression in those cells.
Asunto(s)
Nefropatía Asociada a SIDA , Infecciones por VIH , VIH-1 , Animales , Humanos , Infecciones por VIH/complicaciones , VIH-1/genética , Animales Modificados Genéticamente , Nefropatía Asociada a SIDA/genética , Nefropatía Asociada a SIDA/epidemiología , Nefropatía Asociada a SIDA/patología , Células Epiteliales/patologíaRESUMEN
HIV-1-associated nephropathy (HIVAN) is a severe complication of HIV-1 infection. To gain insight into the pathogenesis of kidney disease in the setting of HIV, a transgenic (Tg) mouse model [CD4C/HIV-negative regulator factor (Nef)] was used in which HIV-1 nef expression is under control of regulatory sequences (CD4C) of the human CD4 gene, thus allowing expression in target cells of the virus. These Tg mice develop a collapsing focal segmental glomerulosclerosis associated with microcystic dilatation, similar to human HIVAN. To identify kidney cells permissive to the CD4C promoter, CD4C reporter Tg lines were used. They showed preferential expression in glomeruli, mainly in mesangial cells. Breeding CD4C/HIV Tg mice on 10 different mouse backgrounds showed that HIVAN was modulated by host genetic factors. Studies of gene-deficient Tg mice revealed that the presence of B and T cells and that of several genes was dispensable for the development of HIVAN: those involved in apoptosis (Trp53, Tnfsf10, Tnf, Tnfrsf1b, and Bax), in immune cell recruitment (Ccl3, Ccl2, Ccr2, Ccr5, and Cx3cr1), in nitric oxide (NO) formation (Nos3 and Nos2), or in cell signaling (Fyn, Lck, and Hck/Fgr). However, deletion of Src partially and that of Hck/Lyn largely abrogated its development. These data suggest that Nef expression in mesangial cells through hematopoietic cell kinase (Hck)/Lck/Yes novel tyrosine kinase (Lyn) represents important cellular and molecular events for the development of HIVAN in these Tg mice.
Asunto(s)
Nefropatía Asociada a SIDA , Infecciones por VIH , Ratones , Humanos , Animales , Proteínas Tirosina Quinasas/metabolismo , Nefropatía Asociada a SIDA/genética , Nefropatía Asociada a SIDA/patología , Ratones Transgénicos , Infecciones por VIH/complicaciones , Tirosina , Familia-src Quinasas , Proteínas Proto-Oncogénicas c-hckRESUMEN
The spectrum of HIV-associated kidney disease has expanded significantly with the introduction of antiretroviral therapy (ART). In the pre-ART era there was prominence of HIV-associated nephropathy (HIVAN). More recently, the spectrum of disease additionally reflects comorbid illness in the ageing HIV population and ART-related nephrotoxicity. We performed a clinicopathological correlation of kidney disease in HIV-positive individuals who underwent kidney biopsy between 1989 and 2014, utilizing the 2018 Kidney Disease Improving Global Outcomes pathologic classification. ART rollout began in 2004 in South Africa. Patients biopsied pre-ART rollout were compared to those biopsied post-ART rollout with respect to demographics, clinical parameters and histology. We assessed kidney survival in a cohort of these patients following biopsy. Six hundred and ninety biopsies were included, 99 (14.3%) were undertaken pre- and 591 (85.7%) post-ART rollout. Most patients were of Black African descent (97.5%). The post-ART rollout patients were older (p = 0.007), had higher eGFR at presentation (p = 0.016) and fewer presented with eGFR of less than 15ml/min/1.73m2 (p = 0.0008). There was a decrease in the prevalence of classic HIVAN (p = 0.00001); and an increase in FSGS (NOS) in the setting of HIV (p = 0.0022) and tubulointerstitial diseases (p = 0.009) post-ART rollout. Kidney function survival over 5 years was poorest in patients with classic HIVAN (p = 0.00005) and best in minimal change nephropathy (p = 0.0013). Kidney biopsy is crucial for the correct diagnosis and management of HIV-related kidney disease. ART rollout has shifted the spectrum of kidney disease away from classic HIVAN but has not eliminated it. Histological diagnosis prognosticates kidney survival.
Asunto(s)
Nefropatía Asociada a SIDA , Infecciones por VIH , Nefropatía Asociada a SIDA/patología , Estudios de Cohortes , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Riñón/patología , PrevalenciaRESUMEN
The achievement of an HIV cure is dependent on the eradication or permanent silencing of HIV-latent viral reservoirs, including the understudied central nervous system (CNS) reservoir. This requires a deep understanding of the molecular mechanisms of HIV's entry into the CNS, latency establishment, persistence, and reversal. Therefore, representative CNS culture models that reflect the intercellular dynamics and pathophysiology of the human brain are urgently needed in order to study the CNS viral reservoir and HIV-induced neuropathogenesis. In this study, we characterized a human cerebral organoid model in which microglia grow intrinsically as a CNS culture model to study HIV infection in the CNS. We demonstrated that both cerebral organoids and isolated organoid-derived microglia (oMG), infected with replication-competent HIVbal reporter viruses, support productive HIV infection via the CCR5 co-receptor. Productive HIV infection was only observed in microglial cells. Fluorescence analysis revealed microglia as the only HIV target cell. Susceptibility to HIV infection was dependent on the co-expression of microglia-specific markers and the CD4 and CCR5 HIV receptors. Altogether, this model will be a valuable tool within the HIV research community to study HIV-CNS interactions, the underlying mechanisms of HIV-associated neurological disorders (HAND), and the efficacy of new therapeutic and curative strategies on the CNS viral reservoir.
Asunto(s)
Nefropatía Asociada a SIDA , Infecciones por VIH , VIH-1 , Microglía , Nefropatía Asociada a SIDA/patología , VIH-1/fisiología , Humanos , Organoides/virología , Receptores del VIHRESUMEN
BACKGROUND: HIV-positive persons of African descent are disproportionately affected by chronic kidney disease (CKD). Deterioration to end-stage kidney disease (ESKD) also occurs in this population at a higher frequency. There remains a lot to learn about the genetic susceptibility to CKD in HIV positive patients, and the pathophysiology of progression to ESKD. OBJECTIVES: We will conduct an exploratory genotype-phenotype study in HIV-positive persons with CKD in Aminu Kano Teaching Hospital, Nigeria, to determine blood-based differential gene expression biomarkers in different kidney risk groups according to the KDIGO 2012 criteria. METHODS: We will consecutively screen 150 HIV-positive adults (≥18 years of age) attending the HIV clinic of Aminu Kano Teaching Hospital, Kano, Nigeria, for CKD based on proteinuria and elevation of estimated glomerular filtration rate. Among these, two separate groups of 16 eligible participants each (n = 32) will be selected in the four (4) KDIGO 2012 kidney risk categories. The groups will be matched for age, sex, viral suppression level and antiretroviral (ARV) regimen. In the first group (n = 16), we will determine differential gene expression markers in peripheral blood mononuclear cells using mRNA-sequencing (RNA-Seq). We will validate the differential expression markers in the second group (n = 16) using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Using a systems-based approach, we will construct, visualize and analyze gene-gene interaction networks to determine the potential biological roles of identified differential expression markers based on published literature and publicly available databases. RESULTS: Our exploratory study will provide valuable information on the potential roles of differential expression biomarkers in the pathophysiology of HIV-associated kidney disease by identifying novel biomarkers in different risk categories of CKD in a sub-Saharan African population. The results of this study will provide the basis for population-based genome-wide association studies to guide future personalized medicine approaches. CONCLUSION: Validated biomarkers can be potential targets for the development of stage-specific therapeutic interventions, an essential paradigm in precision medicine.
Asunto(s)
Nefropatía Asociada a SIDA/patología , Biomarcadores/análisis , Población Negra/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Leucocitos Mononucleares/patología , Polimorfismo de Nucleótido Simple , Nefropatía Asociada a SIDA/epidemiología , Nefropatía Asociada a SIDA/genética , África del Sur del Sahara/epidemiología , Progresión de la Enfermedad , Tasa de Filtración Glomerular , Humanos , Leucocitos Mononucleares/metabolismo , RNA-SeqRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Asunto(s)
Nefropatía Asociada a SIDA/tratamiento farmacológico , Modelos Animales de Enfermedad , Fibrosis/prevención & control , Inflamación/prevención & control , MAP Quinasa Quinasa Quinasa 5/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteinuria/prevención & control , Nefropatía Asociada a SIDA/metabolismo , Nefropatía Asociada a SIDA/patología , Animales , Ratones , Ratones TransgénicosRESUMEN
HIV-associated nephropathy (HIVAN) remains a concern among untreated HIV patients, notably of African descent, as patients can reach end-stage renal disease within 3 years. Two variants (G1 and G2) of the APOL1 gene, common in African populations to protect against African sleeping sickness, have been associated with an increased risk of several glomerular disorders including HIVAN, hypertension-attributed chronic kidney disease, and idiopathic focal segmental glomerulosclerosis and are accordingly named renal risk variants (RRVs). This review examines the mechanisms by which APOL1 RRVs drive glomerular injury in the setting of HIV infection and their potential application to patient management. Innate antiviral mechanisms activated by chronic HIV infection, especially those involving type 1 interferons, are of particular interest as they have been shown to upregulate APOL1 expression. Additionally, the downregulation of miRNA 193a (a repressor of APOL1) is also associated with the upregulation of APOL1. Interestingly, glomerular damage affected by APOL1 RRVs is caused by both loss- and gain-of-function changes in the protein, explicitly characterizing these effects. Their intracellular localization offers a further understanding of the nuances of APOL1 variant effects in promoting renal disease. Finally, although APOL1 variants have been recognized as a critical genetic player in mediating kidney disease, there are significant gaps in their application to patient management for screening, diagnosis, and treatment.
Asunto(s)
Nefropatía Asociada a SIDA/genética , Apolipoproteína L1/genética , Infecciones por VIH/genética , MicroARNs/genética , Nefropatía Asociada a SIDA/complicaciones , Nefropatía Asociada a SIDA/patología , Nefropatía Asociada a SIDA/virología , Variación Genética/genética , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/virología , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Infecciones por VIH/virología , Humanos , Riñón/metabolismo , Riñón/patología , Riñón/virología , Factores de RiesgoRESUMEN
Modern antiretroviral therapies (ART) have decreased the prevalence of HIV-associated nephropathy (HIVAN). Nonetheless, we continue to see children and adolescents with HIVAN all over the world. Furthermore, once HIVAN is established in children, it is difficult to revert its long-term progression, and we need better animal models of childhood HIVAN to test new treatments. To define whether the HIV-1 trans-activator (Tat) gene precipitates HIVAN in young mice, and to develop an inducible mouse model of childhood HIVAN, an HIV-Tat gene cloned from a child with HIVAN was used to generate recombinant adenoviral vectors (rAd-Tat). rAd-Tat and LacZ control vectors (2×109) were expressed in the kidney of newborn wild-type and HIV-transgenic (Tg26) FVB/N mice without significant proteinuria (n=5; 8 per group). Mice were sacrificed 7 and 35â days later to assess their renal outcome, the expression of HIV-genes and growth factors, and markers of cell growth and differentiation by RT-qPCR, immunohistochemistry and/or western blots. HIV-Tat induced the expression of HIV-1 genes and heparin-binding growth factors in the kidney of HIV-Tg26 mice, and precipitated HIVAN in the first month of life. No significant renal changes were detected in wild-type mice infected with rAd-Tat vectors, suggesting that HIV-Tat alone does not induce renal disease. This new mouse model of childhood HIVAN highlights the critical role that HIV-Tat plays in the pathogenesis of HIVAN, and could be used to study the pathogenesis and treatment of HIVAN in children and adolescents.
Asunto(s)
Nefropatía Asociada a SIDA/patología , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/metabolismo , Nefropatía Asociada a SIDA/genética , Albuminuria/complicaciones , Albuminuria/genética , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Apoptosis , Desdiferenciación Celular , Proliferación Celular , Niño , Modelos Animales de Enfermedad , Factor 2 de Crecimiento de Fibroblastos/genética , Factor 2 de Crecimiento de Fibroblastos/metabolismo , VIH-1/genética , Humanos , Riñón/lesiones , Riñón/patología , Ratones Transgénicos , Podocitos/metabolismo , Podocitos/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , beta-Galactosidasa/metabolismo , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismo , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/químicaRESUMEN
We previously used global Hipk2-null mice in various models of kidney disease to demonstrate the central role of homeodomain-interacting protein kinase 2 (HIPK2) in renal fibrosis development. However, renal tubular epithelial cell-specific (RTEC-specific) HIPK2 function in renal fibrogenesis has yet to be determined. Here, we show that modulation of tubular HIPK2 expression and activity affects renal fibrosis development in vivo. The loss of HIPK2 expression in RTECs resulted in a marked diminution of renal fibrosis in unilateral ureteral obstruction (UUO) mouse models and HIV-associated nephropathy (HIVAN) mouse models, which was associated with the reduction of Smad3 activation and downstream expression of profibrotic markers. Conversely, WT HIPK2 overexpression in RTECs accentuated the extent of renal fibrosis in the setting of UUO, HIVAN, and folic acid-induced nephropathy in mice. Notably, kinase-dead HIPK2 mutant overexpression or administration of BT173, an allosteric inhibitor of HIPK2-Smad3 interaction, markedly attenuated the renal fibrosis in these mouse models of kidney disease, indicating that HIPK2 requires both the kinase activity and its interaction with Smad3 to promote TGF-ß-mediated renal fibrosis. Together, these results establish an important RTEC-specific role of HIPK2 in kidney fibrosis and further substantiate the inhibition of HIPK2 as a therapeutic approach against renal fibrosis.
Asunto(s)
Nefropatía Asociada a SIDA/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Insuficiencia Renal Crónica/metabolismo , Nefropatía Asociada a SIDA/patología , Animales , Fibrosis , Humanos , Túbulos Renales/metabolismo , Túbulos Renales/patología , Mutación con Pérdida de Función , Ratones , Ratones Endogámicos C57BL , Proteínas Serina-Treonina Quinasas/genética , Insuficiencia Renal Crónica/patología , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
OBJECTIVES: HIV-1 can infect and persist in different organs and tissues, resulting in the generation of multiple viral compartments and reservoirs. Increasing evidence supports the kidney as such a reservoir. Previous work demonstrated that HIV-1 infected CD4 T-cells transfer virus to renal tubule epithelial (RTE) cells through cell-to-cell contact. In addition to CD4 T cells, macrophages represent the other major target of HIV-1. Renal macrophages induce and regulate inflammatory responses and are critical to homeostatic regulation of the kidney environment. Combined with their ability to harbour virus, macrophages may also play an important role in the spread of HIV-1 infection in the kidney. DESIGN AND METHODS: Multiparametric histochemistry analysis was performed on kidney biopsies from individuals with HIV-1 associated nephropathy (HIVAN). Primary monocyte-derived macrophages were infected with a GFP-expressing replication competent HIV-1. HIV-1 transfer from macrophages to RTE cells was carried out in a coculture system and evaluated by fluorescence-microscopy and flow-cytometry. Live imaging was performed to assess the fate of HIV-1 infected RTE cells over time. RESULTS: We show that macrophages are abundantly present in the renal inflammatory infiltrate of individuals with HIVAN. We observed contact-dependent HIV-1 transfer from infected macrophages to both primary and immortalized renal cells. Live imaging of HIV-1 infected RTE cells revealed four different fates: proliferation, hypertrophy, latency and cell death. CONCLUSION: Our study suggests that macrophages may play a role in the dissemination of HIV-1 in the kidney and that proliferation of infected renal cells may contribute to HIV-1 persistence in this compartment.
Asunto(s)
Nefropatía Asociada a SIDA/virología , Células Epiteliales/fisiología , Células Epiteliales/virología , Infecciones por VIH/diagnóstico , Túbulos Renales/virología , Riñón/virología , Macrófagos/virología , Nefropatía Asociada a SIDA/patología , Linfocitos T CD4-Positivos , Proliferación Celular , Humanos , Estudios Retrospectivos , Latencia del Virus , Replicación ViralRESUMEN
The scenario of infection by the human immunodeficiency virus (HIV) has been undergoing changes in recent years, both in relation to the understanding of HIV infection and regarding the treatments available. As a result, the disease, which before was associated with high morbidity and mortality, is now seen as a chronic disease that can be controlled, regarding both transmission and symptoms. However, even when the virus replication is well controlled, the infected patient remains at high risk of developing renal involvement, either by acute kidney injury not associated with HIV, nephrotoxicity due to antiretroviral drugs, chronic diseases associated with increased survival, or glomerular disease associated to HIV. This review will cover the main aspects of kidney failure associated with HIV.
Asunto(s)
Nefropatía Asociada a SIDA/etiología , Lesión Renal Aguda/etiología , Infecciones por VIH/complicaciones , Nefropatía Asociada a SIDA/patología , Lesión Renal Aguda/patología , Fármacos Anti-VIH/efectos adversos , Terapia Antirretroviral Altamente Activa/efectos adversos , Sulfato de Atazanavir/efectos adversos , Enfermedad Crónica , Infecciones por VIH/tratamiento farmacológico , Humanos , Riñón/patología , Factores de Riesgo , Tenofovir/efectos adversosRESUMEN
SUMMARY The scenario of infection by the human immunodeficiency virus (HIV) has been undergoing changes in recent years, both in relation to the understanding of HIV infection and regarding the treatments available. As a result, the disease, which before was associated with high morbidity and mortality, is now seen as a chronic disease that can be controlled, regarding both transmission and symptoms. However, even when the virus replication is well controlled, the infected patient remains at high risk of developing renal involvement, either by acute kidney injury not associated with HIV, nephrotoxicity due to antiretroviral drugs, chronic diseases associated with increased survival, or glomerular disease associated to HIV. This review will cover the main aspects of kidney failure associated with HIV.
RESUMO O panorama da infecção pelo vírus da imunodeficiência humana (HIV) vem sofrendo alterações nos últimos anos, tanto em relação ao entendimento da infecção pelo HIV quanto aos tratamentos disponíveis. Como resultado, a doença, que antes estava associada a alta morbimortalidade, é agora considerada uma doença crônica que pode ser controlada, tanto em relação à transmissão quanto aos sintomas. No entanto, mesmo quando a replicação viral é bem controlada, o paciente infectado tem um alto risco de desenvolver complicações renais, seja através de lesão renal aguda não relacionada ao HIV, por nefrotoxicidade causada por drogas antirretrovirais, por doenças crônicas associadas com o aumento da sobrevida ou por doença glomerular associada ao HIV. Esta revisão abordará os principais aspectos da insuficiência renal associada ao HIV.
Asunto(s)
Humanos , Infecciones por VIH/complicaciones , Nefropatía Asociada a SIDA/etiología , Lesión Renal Aguda/etiología , Infecciones por VIH/tratamiento farmacológico , Enfermedad Crónica , Factores de Riesgo , Nefropatía Asociada a SIDA/patología , Fármacos Anti-VIH/efectos adversos , Terapia Antirretroviral Altamente Activa/efectos adversos , Lesión Renal Aguda/patología , Tenofovir/efectos adversos , Sulfato de Atazanavir/efectos adversos , Riñón/patologíaRESUMEN
HIV-associated nephropathy (HIVAN) is a rapidly progressive kidney disease that is caused by HIV infection of renal epithelial cells with subsequent expression of viral genes, including vpr. Antiretroviral therapy ameliorates HIVAN without eradicating HIV from the kidneys and the mechanism by which it protects kidneys is poorly understood. Since HIV protease inhibitors have "off target" cellular effects, we studied whether darunavir, the most commonly prescribed protease inhibitor, protects kidneys from HIV-induced injury via mechanisms independent of HIV protease and viral replication. Renal epithelial cells were transduced with lentiviruses encoding HIV (lacking protease and reverse transcriptase), Vpr, or vector control. Darunavir attenuated HIV and Vpr-induced activation of Stat3, Src, Erk, and cytokines, which are critical for HIVAN pathogenesis. We then studied HIV-transgenic mice, which develop HIVAN in the absence of HIV protease or reverse transcriptase. Mice were treated with darunavir, zidovudine, darunavir + zidovudine, or control. Darunavir and darunavir + zidovudine reduced albuminuria and histologic kidney injury and normalized expression of dysregulated proteins. RNA-seq analyses demonstrated that darunavir suppressed HIV-induced upregulation of immune response genes in human kidney cells. These data demonstrate that darunavir protects against HIV-induced renal injury via mechanisms that are independent of inhibition of HIV protease.
Asunto(s)
Nefropatía Asociada a SIDA/prevención & control , Darunavir/farmacología , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/metabolismo , Riñón/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Nefropatía Asociada a SIDA/metabolismo , Nefropatía Asociada a SIDA/patología , Animales , Línea Celular , Humanos , Riñón/patología , Riñón/virología , Ratones , Ratones Transgénicos , Zidovudina/farmacologíaRESUMEN
In nearly 40 years since human immunodeficiency virus (HIV) first emerged, much has changed. Our understanding of the pathogenesis of HIV infection and its effect on the cells within each kidney compartment has progressed, and the natural history of the disease has been transformed. What was once an acutely fatal illness is now a chronic disease managed with oral medications. This change is largely due to the advent of antiretroviral drugs, which have dramatically altered the prognosis and progression of HIV infection. However, the success of antiretroviral therapy has brought with it new challenges for the nephrologist caring for patients with HIV/acquired immune deficiency syndrome, including antiretroviral therapy-induced nephrotoxicity, development of non-HIV chronic kidney disease, and rising incidence of immune-mediated kidney injury. In this review, we discuss the pathogenesis of HIV infection and how it causes pathologic changes in the kidney, review the nephrotoxic effects of select antiretroviral medications, and touch upon other causes of kidney injury in HIV cases, including mechanisms of acute kidney injury, HIV-related immune complex glomerular disease, and thrombotic microangiopathy.
Asunto(s)
Nefropatía Asociada a SIDA/virología , Fármacos Anti-VIH/efectos adversos , Glomerulonefritis/virología , Infecciones por VIH/tratamiento farmacológico , Enfermedades del Complejo Inmune/virología , Microangiopatías Trombóticas/virología , Nefropatía Asociada a SIDA/etiología , Nefropatía Asociada a SIDA/genética , Nefropatía Asociada a SIDA/patología , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/etiología , Fármacos Anti-VIH/uso terapéutico , Predisposición Genética a la Enfermedad , Glomerulonefritis/etiología , Glomerulonefritis/inmunología , Infecciones por VIH/complicaciones , Humanos , Enfermedades del Complejo Inmune/etiología , Enfermedades del Complejo Inmune/inmunología , Insuficiencia Renal Crónica/complicaciones , Microangiopatías Trombóticas/etiologíaRESUMEN
BACKGROUND: The aim of this study was to assess, the efficacy and safety of add-on corticosteroids to antiretroviral therapy [ART] in patients with biopsy proven HIV associated nephropathy. METHODS: All included patients had histological evidence of either collapsing or non-collapsing focal segmental glomerulosclerosis (FSGS) or podocyte and/or parietal cell hypertrophy or hyperplasia. All patients had evidence of tubulointerstitial inflammation with microcysts. Patients were randomized to ART with the addition of 1 mg/kg of corticosteroids [ART+C] or remained in the group [ART Alone] and followed for 2 years. A repeat biopsy was performed at 6 months. RESULTS: Twenty-one patients were randomized to [ART+C] and 17 to [ART Alone]. The baseline estimated glomerular filtration rate (eGFR) was significantly lower in the [ART+C] vs. [ART Alone] group [35mls/min/1.73m2 vs. 47 mls/min/1.73m2, p = 0.015]. The [ART+C] cohort had a statistically significant improvement in median (eGFR) from baseline to last follow up compared with [ART Alone] i.e. [Δ = 25mls/min (IQR: 15;51) vs 9 mls/min (IQR: 0-24), p = 0.008]. There were no statistically significant differences between the groups when proteinuria and histology were analyzed. There were 8 deaths during the trial period, 7 from [ART+C] (Log rank p = 0.071). CONCLUSIONS: In the [ART+C] cohort there was a significant improvement in eGFR over 2-years with increased mortality. Routine corticosteroid use cannot currently be recommended. Further investigation to define which subgroup of this cohort would safely benefit from the positive effects is required. TRIAL REGISTRATION: ISRCTN study ID ( 56112439 ] was retrospectively registered on the 5 September 2018.
Asunto(s)
Nefropatía Asociada a SIDA/tratamiento farmacológico , Prednisona/uso terapéutico , Nefropatía Asociada a SIDA/epidemiología , Nefropatía Asociada a SIDA/patología , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Biopsia , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Glomeruloesclerosis Focal y Segmentaria/epidemiología , Glomeruloesclerosis Focal y Segmentaria/etiología , Glomeruloesclerosis Focal y Segmentaria/patología , Humanos , Estimación de Kaplan-Meier , Riñón/efectos de los fármacos , Riñón/fisiopatología , Masculino , Prednisona/administración & dosificación , Prednisona/efectos adversos , Estudios Prospectivos , Sudáfrica/epidemiología , Resultado del Tratamiento , Tuberculosis/complicacionesRESUMEN
Human immunodeficiency virus associated nephropathy (HIVAN) is a unique form of a renal parenchymal disorder. This disease and its characteristics can be accredited to incorporation of DNA and mRNA of human immunodeficiency virus type 1 into the renal parenchymal cells. A proper understanding of the intricacies of HIVAN and the underlying mechanisms associated with renal function and disorders is vital for the potential development of a reliable treatment for HIVAN. Specifically, the renal tubule segment of the kidney is characterized by its transport capabilities and its ability to reabsorb water and salts into the blood. However, the segment is also known for certain disorders, such as renal tubular epithelial cell infection and microcyst formation, which are also closely linked to HIVAN. Furthermore, certain organelles, like the endoplasmic reticulum (ER), mitochondria, and lysosome, are vital for certain underlying mechanisms in kidney cells. A paradigm of the importance of said organelles can be seen in documented cases of HIVAN where the renal disorder results increased ER stress due to HIV viral propagation. This balance can be restored through the synthesis of secretory proteins, but, in return, the secretion requires more energy; therefore, there is a noticeable increase in mitochondrial stress. The increased ER changes and mitochondrial stress will greatly upregulate the process of autophagy, which involves the cell's lysosomes. In conjunction, we found that ER stress and mitochondrial changes are associated in the Tg26 animal model of HIVAN. The aim of our review is to consolidate current knowledge of important mechanisms in HIVAN, specifically related to the renal tubules' association with ER stress, mitochondrial changes and autophagy. Although the specific regulatory mechanism detailing the cross-talk between the various organelles is unknown in HIVAN, the continued research in this field may potentially shed light on a possible improved treatment for HIVAN.
Asunto(s)
Nefropatía Asociada a SIDA/patología , Autofagia , Estrés del Retículo Endoplásmico , Túbulos Renales/patología , Mitocondrias/patología , Nefropatía Asociada a SIDA/cirugía , Acidosis Tubular Renal/patología , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacología , Humanos , Necrosis de la Corteza Renal/patología , Trasplante de Riñón , Túbulos Renales/fisiopatología , Túbulos Renales/ultraestructuraRESUMEN
OBJECTIVE: To investigate the association of mild renal impairment and coronary plaque in people living with HIV (PLHIV). METHODS: PLHIV and non-HIV controls with serum creatinine less than 1.5âmg/dl were investigated. Estimated glomerular filtration rate (eGFR) (calculated by CKD-EPI formula) was related to coronary plaque indices obtained by CT angiography. RESULTS: One hundred and eighty-four PLHIV [HIV viral load, 49 (47,49) copies/ml, CD4+ cell count, median 536 (370, 770) cells/µl, duration HIV, 15â±â7 years] and 72 HIV-negative controls without known cardiovascular disease (CVD) were studied. The two groups were well matched for traditional CVD risk factors. Serum creatinine (0.9â±â0.2 vs. 0.9â±â0.2âmg/dl, Pâ=â0.96) and eGFR (96â±â22 vs. 96â±â24âml/min per 1.73âm(2), Pâ=â0.99) were similar between PLHIV and non-HIV, respectively. In PLHIV, eGFR inversely related to total severity of coronary plaque score (râ=â-0.27, Pâ=â0.002), total coronary segments with plaque (râ=â-0.21, Pâ=â0.005), calcified plaque segments (râ=â-0.15, Pâ=â0.045), and Agatston score (râ=â-0.21, Pâ=â0.006). Adjusting for total Framingham point score, BMI, and HIV parameters, eGFR remained significantly associated with calcified plaque and Agatston score in PLHIV. In HIV negative controls, eGFR did not correlate with calcified plaque (râ=â-0.20, Pâ=â0.10) or Agatston score (râ=â-0.13, Pâ=â0.29). Among PLHIV, those with eGFR less than 90âml/min per 1.73âm(2) demonstrated increased total severity of coronary plaque score compared with those with eGFR greater than or equal to 90, Pâ=â0.02). This relationship was stronger in PLHIV than the non-HIV group. CONCLUSION: Our data highlight a robust relationship between subclinical renal impairment and coronary artery disease among PLHIV. Further research is needed to understand the relationship between mild renal impairment and CVD in HIV.