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Revista Da Associacao Medica Brasileira... Jan 2020The 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... (Review)
Review
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.
Topics: AIDS-Associated Nephropathy; Acute Kidney Injury; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Chronic Disease; HIV Infections; Humans; Kidney; Risk Factors; Tenofovir
PubMed: 31939539
DOI: 10.1590/1806-9282.66.S1.75 -
Disease Models & Mechanisms Dec 2019Notch pathway activation plays a central role in the pathogenesis of many glomerular diseases. We have previously shown that Notch4 expression was upregulated in various...
Notch pathway activation plays a central role in the pathogenesis of many glomerular diseases. We have previously shown that Notch4 expression was upregulated in various renal cells in human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) patients and rodent models of HIVAN. In this study, we examined whether the Notch pathway can be distinctly activated by HIV-1 gene products and whether Notch4, in particular, can influence disease progression. Using luciferase reporter assays, we did not observe activation of the promoter with the HIV protein Nef in podocytes. Further, we observed upregulated expression of a gamma secretase complex protein, presenilin 1, but not Notch4, in podocytes infected with an HIV-1 expression construct. To assess the effects of Notch4 on HIVAN disease progression, we engineered Tg26 mice with global deletion of the Notch4 intracellular domain ( ), which is required for signaling function. These mice ( ) showed a significant improvement in renal function and a significant decrease in mortality compared to Tg26 mice. Histological examination of kidneys showed that mice had overall glomerular, tubulointerstitial injury and a marked decrease in interstitial inflammation. A significant decrease in the proliferating cells was observed in the tubulointerstitial compartments of mice. Consistent with the diminished inflammation, kidneys from mice also showed a significant decrease in expression of the inflammatory cytokine transcripts and , as well as the master inflammatory transcription factor NF-κB ( transcripts and p65 protein). These data identify Notch4 as an important mediator of tubulointerstitial injury and inflammation in HIVAN and a potential therapeutic target.
Topics: AIDS-Associated Nephropathy; Animals; Cell Proliferation; Crosses, Genetic; Disease Models, Animal; Disease Progression; Female; Gene Deletion; HEK293 Cells; Humans; Inflammation; Kidney; Male; Mice; Mice, Transgenic; NF-kappa B p50 Subunit; Podocytes; Receptor, Notch4; Signal Transduction; Transcription Factor RelA; Treatment Outcome; nef Gene Products, Human Immunodeficiency Virus
PubMed: 31727625
DOI: 10.1242/dmm.040642 -
Scientific Reports Nov 2019HIV-associated nephropathy (HIVAN) is a rapidly progressive kidney disease that is caused by HIV infection of renal epithelial cells with subsequent expression of viral...
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.
Topics: AIDS-Associated Nephropathy; Animals; Cell Line; Darunavir; HIV Protease Inhibitors; HIV-1; Humans; Kidney; MAP Kinase Signaling System; Mice; Mice, Transgenic; Zidovudine
PubMed: 31676833
DOI: 10.1038/s41598-019-52278-3 -
PloS One 2019African polymorphisms in the gene for Apolipoprotein L1 (APOL1) confer a survival advantage against lethal trypanosomiasis but also an increased risk for several chronic...
African polymorphisms in the gene for Apolipoprotein L1 (APOL1) confer a survival advantage against lethal trypanosomiasis but also an increased risk for several chronic kidney diseases (CKD) including HIV-associated nephropathy (HIVAN). APOL1 is expressed in renal cells, however, the pathogenic events that lead to renal cell damage and kidney disease are not fully understood. The podocyte function of APOL1-G0 versus APOL1-G2 in the setting of a known disease stressor was assessed using transgenic mouse models. Transgene expression, survival, renal pathology and function, and podocyte density were assessed in an intercross of a mouse model of HIVAN (Tg26) with two mouse models that express either APOL1-G0 or APOL1-G2 in podocytes. Mice that expressed HIV genes developed heavy proteinuria and glomerulosclerosis, and had significant losses in podocyte numbers and reductions in podocyte densities. Mice that co-expressed APOL1-G0 and HIV had preserved podocyte numbers and densities, with fewer morphologic manifestations typical of HIVAN pathology. Podocyte losses and pathology in mice co-expressing APOL1-G2 and HIV were not significantly different from mice expressing only HIV. Podocyte hypertrophy, a known compensatory event to stress, was increased in the mice co-expressing HIV and APOL1-G0, but absent in the mice co-expressing HIV and APOL1-G2. Mortality and renal function tests were not significantly different between groups. APOL1-G0 expressed in podocytes may have a protective function against podocyte loss or injury when exposed to an environmental stressor. This was absent with APOL1-G2 expression, suggesting APOL1-G2 may have lost this protective function.
Topics: AIDS-Associated Nephropathy; Animals; Apolipoprotein L1; Apolipoproteins; Disease Models, Animal; Genetic Predisposition to Disease; Genetic Variation; Humans; Kidney Glomerulus; Mice; Mice, Inbred BALB C; Mice, Transgenic; Podocytes; Polymorphism, Genetic; Renal Insufficiency, Chronic; Transcriptome
PubMed: 31661509
DOI: 10.1371/journal.pone.0224408 -
Cureus Aug 2019Human immunodeficiency virus (HIV) infection presents with a variety of conditions. We describe the case of a 33-year-old Hispanic male with IgA nephropathy and...
Human immunodeficiency virus (HIV) infection presents with a variety of conditions. We describe the case of a 33-year-old Hispanic male with IgA nephropathy and Henoch-Schonlein Purpura in the setting of HIV. The incidence of vasculitis associated with HIV infection is less than 1%. There are few cases reported of IgA nephropathy in the context of HIV. Henoch-Schonlein Purpura usually presents in children. We encountered a patient with rare illnesses while in the setting of immunodeficiency.
PubMed: 31612096
DOI: 10.7759/cureus.5368 -
American Journal of Kidney Diseases :... Dec 2019African Americans have a 2- to 4-fold greater incidence of end-stage kidney disease (ESKD) than whites, which has long raised the possibility of a genetic cause for this... (Review)
Review
African Americans have a 2- to 4-fold greater incidence of end-stage kidney disease (ESKD) than whites, which has long raised the possibility of a genetic cause for this disparity. Recent advances in genetic studies have shown a causal association of polymorphisms at the apolipoprotein L1 gene (APOL1) with the markedly increased risk for the nondiabetic component of the overall disparity in ESKD in African Americans. Although APOL1-associated kidney disease is thought to account for a substantial proportion of ESKD in African Americans, not all the increased risk for ESKD is accounted for, and a complete cataloging of disparities in genetic causes of ESKD eludes our current understanding of genetic-associated kidney disease. Genetic testing aids the screening, diagnosis, prognosis, and treatment of diseases with a genetic basis. Widespread use of genetic testing in clinical practice is limited by the small number of actionable genetic variants, limited health literacy of providers and patients, and underlying complex ethical, legal, and social issues. This perspective reviews racial and ethnic differences associated with genetic diseases and the development of ESKD in African Americans and discusses potential uncertainties associated with our current understanding of penetrance of genetically linked kidney disease and population-attributable risk percent.
Topics: Black or African American; Apolipoprotein L1; Case-Control Studies; Female; Genetic Predisposition to Disease; Genetic Testing; Health Status Disparities; Healthcare Disparities; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Needs Assessment; Renal Dialysis; United States
PubMed: 31606237
DOI: 10.1053/j.ajkd.2019.06.006 -
Journal of Clinical Medicine Sep 2019BK polyomavirus (BKPyV), or BKV infection, is ubiquitous and usually non-pathogenic, with subclinical infections in 80-90% of adults worldwide. BKV infection is often... (Review)
Review
BK polyomavirus (BKPyV), or BKV infection, is ubiquitous and usually non-pathogenic, with subclinical infections in 80-90% of adults worldwide. BKV infection is often associated with pathology in immunocompromised individuals. BKV infection often is associated with renal impairment, including ureteral stenosis, hemorrhagic cystitis, and nephropathy. BKV infection is less commonly associated with pneumonitis, retinitis, liver disease, and meningoencephalitis. BKV is known to replicate, establish latency, undergo reactivation, and induce clinical pathology in renal tubular epithelial cells. However, recent in vitro studies support the notion that BKV has expanded tropism-targeting glomerular parenchymal cells of the human kidney, which could impact glomerular function, enhance inflammation, and serve as viral reservoirs for reactivation from latency during immunosuppression. The implications of BKV expanded tropism in the glomerulus, and how specific host and viral factors that would contribute to glomerular inflammation, cytolysis, and renal fibrosis are related to BKV associated nephropathy (BKVAN), have not been explored. The pathogenesis of BKV in human glomerular parenchymal cells is poorly understood. In this review, I examine target cell populations for BKV infectivity in the human glomerulus. Specifically, I explore the implications of BKV expanded tropism in the glomerulus with regard viral entry, replication, and dissemination via cell types exposed to BKV trafficking in glomerulus. I also describe cellular targets shown to be permissive in vitro and in vivo for BKV infection and lytic replication, the potential role that glomerular parenchymal cells play in BKV latency and/or reactivation after immunosuppression, and the rare occurrence of BKV pathology in glomerular parenchymal cells in patients with BKVAN.
PubMed: 31533282
DOI: 10.3390/jcm8091477 -
HIV Medicine Oct 2019The use of combination antiretroviral therapy (cART) increases clinical uncertainty about changes in renal function. Specifically, little is known regarding the...
Effects of aging, baseline renal function and stage of HIV infection on post-treatment changes in renal function among HIV-infected patients: a retrospective cohort study.
OBJECTIVES
The use of combination antiretroviral therapy (cART) increases clinical uncertainty about changes in renal function. Specifically, little is known regarding the interaction of the effects of aging, baseline renal impairment, and stages of HIV infection on post-treatment changes in renal function.
METHODS
This analysis included 5533 HIV-infected patients on cART in 2004-2016. Progression to chronic kidney disease (CKD) was defined as either two consecutive estimated glomerular filtration rate (eGFR) measurements < 60 mL/min/1.73 m for baseline eGFR ≥ 60 mL/min/1.73 m (mild renal impairment or normal renal function) or a 25% decline for baseline eGFR < 60 mL/min/1.73 m (moderate renal impairment).
RESULTS
During follow-up (median 4.8 years), 130 (2.3%) of the patients progressed to CKD. A total of 20.1% of patients with baseline normal renal function progressed to mild renal impairment, while 74.0% of patients with baseline mild or moderate renal impairment improved to normal renal function. In multivariable analysis, a significant positive baseline-eGFR-by-World Health Organization (WHO)-stage interaction effect on progression to CKD in all patients was identified, indicating a cross-over effect from a reduced risk to an increased risk. A significant negative baseline-age-by-WHO-stage interaction effect on progression to mild renal impairment in patients with baseline normal renal function was identified, with adjusted hazard ratios progressively lower at older ages. In addition, there were significant associations with older age, lower baseline eGFR, Dai ethnic minority, and anaemia for both outcomes, hyperglycaemia for CKD only, and higher CD4 count, tenofovir and ritonavir-boosted lopinavir use for mild renal impairment only.
CONCLUSIONS
Our data suggest a complex pattern of renal function dynamics in patients on cART, which requires precise management with systematic monitoring of the interaction of the effects of sociodemographic, nephrological and HIV-specific clinical characteristics.
Topics: AIDS-Associated Nephropathy; Adult; Aging; Anti-HIV Agents; CD4 Lymphocyte Count; China; Disease Progression; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Treatment Outcome
PubMed: 31274235
DOI: 10.1111/hiv.12763 -
The Journal of Pain 2020Numerous studies have demonstrated a physiological interaction between the mu opioid receptor (MOR) and delta opioid receptor (DOR) systems. A few studies have shown...
Numerous studies have demonstrated a physiological interaction between the mu opioid receptor (MOR) and delta opioid receptor (DOR) systems. A few studies have shown that dual MOR-DOR agonists could be beneficial, with reduced tolerance and addiction liability, but are nearly untested in chronic pain models, particularly neuropathic pain. In this study, we tested the MOR-DOR agonist SRI-22141 in mice in the clinically relevant models of HIV Neuropathy and Chemotherapy-Induced Peripheral Neuropathy (CIPN). SRI-22141 was more potent than morphine in the tail flick pain test and had equal or enhanced efficacy versus morphine in both neuropathic pain models, with significantly reduced tolerance. SRI-22141 also produced no jumping behavior during naloxone-precipitated withdrawal in CIPN or naïve mice, suggesting that SRI-22141 produces little to no dependence. SRI-22141 also reduced tumor necrosis factor-α and cyclooxygenase-2 in CIPN in the spinal cord, suggesting an anti-inflammatory mechanism of action. The DOR-selective antagonist naltrindole strongly reduced CIPN efficacy and anti-inflammatory activity in the spinal cord, without affecting tail flick antinociception, suggesting the importance of DOR activity in these models. Overall, these results provide compelling evidence that MOR-DOR agonists could have strong efficacy with reduced side effects and an anti-inflammatory mechanism in the treatment of neuropathic pain. PERSPECTIVE: This study demonstrates that a MOR-DOR dual agonist given chronically in chronic neuropathic pain models has enhanced efficacy with strongly reduced tolerance and dependence, with a further anti-inflammatory effect in the spinal cord. This suggests that MOR-DOR dual agonists could be effective treatments for neuropathic pain with reduced side effects.
Topics: AIDS-Associated Nephropathy; Analgesics, Opioid; Animals; Anti-Inflammatory Agents; Behavior, Animal; Cell Line; Cricetulus; Disease Models, Animal; Female; Male; Mice; Mice, Inbred ICR; Neuralgia; Neurotoxicity Syndromes; Ovary; Receptors, Opioid, delta; Receptors, Opioid, mu
PubMed: 31201990
DOI: 10.1016/j.jpain.2019.05.017 -
AIDS (London, England) Aug 2019Many of those aging with HIV suffer from distal neuropathic pain (DNP) due to HIV-associated sensory neuropathy (HIV-SN). Prior studies have linked chronic pain... (Observational Study)
Observational Study
BACKGROUND
Many of those aging with HIV suffer from distal neuropathic pain (DNP) due to HIV-associated sensory neuropathy (HIV-SN). Prior studies have linked chronic pain conditions to a variant of the catechol-O-methyltransferase (COMT), ValMet. This variant confers reduced enzymatic activity and results in higher synaptic dopamine levels. Here we examined the role of ValMet as a predictor of DNP in HIV-SN.
METHODS
In 1044 HIV-infected individuals enrolled in CNS HIV Antiretroviral Therapy Effects Research, an observational study across six US institutions, we characterized the relationship between ValMet and DNP in HIV-SN. Participants underwent neurologic examination and genotyping. Stratification into genetic ancestry groups was employed to eliminate bias due to genetic background.
FINDINGS
Of 590 participants with HIV-SN, 38% endorsed DNP, 24% reported nonpainful symptoms of neuropathy (paresthesia and numbness), and 38% were asymptomatic. Compared with asymptomatic HIV-SN, ValMet was associated with 2.3 higher odds of DNP. There were no increased odds of nonpainful symptoms. The association remained significant after controlling for other risk factors for DNP: lifetime diagnosis of depression, older age, ancestry, cumulative exposure to dideoxynucleoside antiretrovirals, diabetes, and nadir CD4. Stratified by genetic ancestry, the association between ValMet and DNP was significant in European and African genetic ancestry.
INTERPRETATION
ValMet may be a genetic marker for susceptibility to DNP in HIV-SN. Our findings support the notion that differences in pain processing mediated by COMT-related dopamine signaling play a role in susceptibility to DNP in HIV-SN. Because prior studies suggest that the COMT allele may influence dose-response relationships with opioid treatment, knowing COMT genotype could influence management.
Topics: AIDS-Associated Nephropathy; Adult; Amino Acid Substitution; Catechol O-Methyltransferase; Female; Genetic Predisposition to Disease; Genotype; Genotyping Techniques; HIV Infections; Humans; Male; Methionine; Middle Aged; Neuralgia; Polymorphism, Single Nucleotide; Prospective Studies; United States; Valine
PubMed: 31021849
DOI: 10.1097/QAD.0000000000002240