Childhood HIV-associated nephropathy: 36 years later.
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ABSTRACT:
SUBMITTER: Ray PE
PROVIDER: S-EPMC8061423 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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 35 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.
| S-EPMC7648609 | biostudies-literature
Project description:The unexpected encounter, 10 years ago, between human immunodeficiency virus (HIV) and the chemokine system has dramatically advanced our understanding of the pathogenesis of AIDS, opening new perspectives for the development of effective prophylactic and therapeutic measures. To initiate infection, the HIV-1 external envelope glycoprotein, gp120, sequentially interacts with two cellular receptors, CD4 and a chemokine receptor (or coreceptor) like CCR5 or CXCR4. This peculiar two-stage receptor-interaction strategy allows gp120 to maintain the highly conserved coreceptor-binding site in a cryptic conformation, protected from neutralizing antibodies. The differential use of CCR5 and CXCR4 defines three HIV-1 biological variants (R5, R5X4, X4), which vary in their prevalence during the disease course. The evolutionary choice of HIV-1 to exploit chemokine receptors as cellular entry gateways has turned their chemokine ligands into endogenous antiviral factors that variably modulate viral transmission, disease progression and vaccine responses. Likewise, the natural history of HIV-1 infection is influenced by specific polymorphisms of chemokine and chemokine-receptor genes. The imminent clinical availability of coreceptor-targeted viral entry inhibitors raises new hope for bridging the gap towards a definitive cure of HIV infection.
| S-EPMC1383531 | biostudies-literature
Project description:Exposure of young animals to commonly used anesthetics causes neurotoxicity including impaired neurocognitive function and abnormal behavior. The potential neurocognitive and behavioral effects of anesthesia exposure in young children are thus important to understand.To examine if a single anesthesia exposure in otherwise healthy young children was associated with impaired neurocognitive development and abnormal behavior in later childhood.Sibling-matched cohort study conducted between May 2009 and April 2015 at 4 university-based US pediatric tertiary care hospitals. The study cohort included sibling pairs within 36 months in age and currently 8 to 15 years old. The exposed siblings were healthy at surgery/anesthesia. Neurocognitive and behavior outcomes were prospectively assessed with retrospectively documented anesthesia exposure data.A single exposure to general anesthesia during inguinal hernia surgery in the exposed sibling and no anesthesia exposure in the unexposed sibling, before age 36 months.The primary outcome was global cognitive function (IQ). Secondary outcomes included domain-specific neurocognitive functions and behavior. A detailed neuropsychological battery assessed IQ and domain-specific neurocognitive functions. Parents completed validated, standardized reports of behavior.Among the 105 sibling pairs, the exposed siblings (mean age, 17.3 months at surgery/anesthesia; 9.5% female) and the unexposed siblings (44% female) had IQ testing at mean ages of 10.6 and 10.9 years, respectively. All exposed children received inhaled anesthetic agents, and anesthesia duration ranged from 20 to 240 minutes, with a median duration of 80 minutes. Mean IQ scores between exposed siblings (scores: full scale?=?111; performance?=?108; verbal?=?111) and unexposed siblings (scores: full scale?=?111; performance?=?107; verbal?=?111) were not statistically significantly different. Differences in mean IQ scores between sibling pairs were: full scale?=?-0.2 (95% CI, -2.6 to 2.9); performance?=?0.5 (95% CI, -2.7 to 3.7); and verbal?=?-0.5 (95% CI, -3.2 to 2.2). No statistically significant differences in mean scores were found between sibling pairs in memory/learning, motor/processing speed, visuospatial function, attention, executive function, language, or behavior.Among healthy children with a single anesthesia exposure before age 36 months, compared with healthy siblings with no anesthesia exposure, there were no statistically significant differences in IQ scores in later childhood. Further study of repeated exposure, prolonged exposure, and vulnerable subgroups is needed.
| S-EPMC5316422 | biostudies-literature
Project description:BackgroundHuman immunodeficiency virus-associated nephropathy (HIVAN) is the most common cause of end stage kidney disease (ESKD) in human immunodeficiency virus-1 (HIV-1) serotype patients and it mostly affects patients of African descent. It rapidly progresses to ESKD if untreated. The goal of treatment is directed toward reducing HIV-1 replication and/or slowing the progression of chronic kidney disease. The following pharmacological agents have been used for the treatment of HIVAN: antiretroviral therapy, angiotensin-converting enzyme inhibitors (ACEi), steroids and recently cyclosporin. Despite this, the effect of each intervention is yet to be evaluated.ObjectivesTo evaluate the benefits and harms of adjunctive therapies in the management of HIVAN and its effects on symptom severity and all-cause mortality.Search methodsIn January 2012 we searched the Cochrane Renal Group's Specialised Register, AIDS Education Global Information System (AEGIS database), ClinicalTrial.gov, the WHO International Clinical Trials Registry Portal, and reference lists of retrieved articles without language restrictions. In our original review we searched CENTRAL, MEDLINE, EMBASE, and AIDSearch, in addition to contacting individual researchers, research organisations and pharmaceutical companies.Selection criteriaRandomised controlled trials (RCTs) and quasi-RCTs of any therapy used in the treatment of HIVAN.Data collection and analysisWe independently screened the search outputs for relevant studies and to retrieve full articles when necessary. For dichotomous outcomes results were to be expressed as risk ratios with 95% confidence intervals, and for continuous scales of measurement the mean difference was to be used.Main resultsWe identified four relevant ongoing studies: one is still ongoing; two have completed recruitment but are yet to be published; and the fourth study was suspended for unspecified reasons. No completed RCTs or quasi-RCTs were identified. We summarised and tabulated the data from the observational studies, however no formal analyses were performed.Authors' conclusionsThere is currently no RCT-based evidence upon which to base guidelines for the treatment of HIVAN, however three ongoing studies have been identified. Data from observational studies suggest steroids and angiotensin-converting enzyme inhibitors appear to improve kidney function in patients with HIVAN, however no formal analyses were performed in this review. This review highlights the need for good quality RCTs to address the effects of interventions for treating this group.
| S-EPMC7209266 | biostudies-literature
Project description:ImportanceFew studies have examined the association between underweight in the first 2 years and growth in later childhood in high-income countries.ObjectiveTo evaluate the associations of underweight in the first 2 years of life with body mass index (calculated as weight in kilograms divided by height in meters squared) z score (zBMI), weight-for-age z score (WAZ), and height-for-age z score (HAZ) from ages 2 to 10 years.Design, setting, and participantsThis prospective cohort study was conducted between February 2008 to September 2020 in The Applied Research Group for Kids! practice-based research network in Toronto, Canada. Participants included healthy children aged 0 to 10 years. Data were analyzed from October 2020 to December 2021.ExposuresUnderweight (ie, zBMI less than -2, per the World Health Organization) in the first 2 years of life.Main outcomes and measuresThe primary outcome was zBMI from ages 2 to 10 years. Linear mixed-effects models were used to account for multiple growth measures over time.ResultsA total of 5803 children were included in the primary analysis. At baseline, the mean (SD) age was 4.07 (5.62) months, 2982 (52.2%) were boys, and 550 children (9.5%) were underweight. Underweight in the first 2 years was associated with lower zBMI (difference, -0.39 [95% CI, -0.48 to -0.31]) at 10 years and lower HAZ (difference, -0.24 [95% CI, -0.34 to -0.14]) at age 2 years. Stratified by sex, at age 10 years, girls and boys with underweight in the first 2 years both had lower zBMI (girls: difference, -0.47 [95% CI, -0.59 to -0.34]; boys: difference, -0.32 [95% CI, -0.44 to -0.20]). At age 10 years, children with underweight and a lower zBMI growth rate in the first 2 years had lower zBMI (difference, -0.64 [95% CI, -0.77 to -0.53) and HAZ (difference, -0.12 [-0.24 to -0.01]), while children with underweight and a higher zBMI growth rate in the first 2 years had similar zBMI (difference, -0.11 [95% CI, -0.22 to 0.001]) and higher HAZ (difference, 0.16 [95% CI, 0.05 to 0.27]) compared with children who did not have underweight in the first 2 years.Conclusions and relevanceIn this prospective cohort study, children with underweight in the first 2 years of life had lower zBMI and HAZ in later childhood. These associations were attenuated among children with a higher growth rate in the first 2 years.
| S-EPMC9338407 | biostudies-literature
Project description:Epidemiological research reveals that insufficient sleep in children has negative cognitive and emotional consequences; however, the physiological underpinnings of these observations remain understudied. We tested the hypothesis that the topographical distribution of deep sleep slow wave activity during the childhood predicts brain white matter microstructure (myelin) 3.5 y later. Healthy children underwent sleep high-density EEG at baseline (n = 13; ages 2.4-8.0 y) and follow-up (n = 14; ages 5.5-12.2 y). At follow-up, myelin (myelin water fraction) and cortical morphology were also quantified. Our investigation revealed 3 main findings. (1) The Frontal/Occipital (F/O)-ratio at baseline strongly predicted whole brain myelin at follow-up. (2) At follow-up, the F/O-ratio was only minimally (negatively) linked to brain myelin. (3) Cortical morphology was not related to the F/O-ratio, neither at baseline nor at follow-up. Our results support the hypothesis that during child development EEG markers during sleep longitudinally predict brain myelin content. Data extend previous findings reporting a link between EEG markers of sleep need and cortical morphology, by supporting the hypothesis that sleep is a necessary component to underlying processes of brain, and specifically myelin, maturation. In line with the overarching theory that sleep contributes to neurodevelopmental processes, it remains to be investigated whether chronic sleep loss negatively affects white matter myelin microstructure growth during sensitive periods of development.
| S-EPMC6688908 | biostudies-literature
Project description:In developed countries, remarkable advances in antiretroviral therapy have transformed HIV infection into a chronic condition. As a result, HIV-associated nephropathy, the classic HIV-driven kidney lesion among individuals of African descent, has largely disappeared in these regions. However, HIV-positive blacks continue to have much higher rates of ESRD than HIV-positive whites, which could be attributed to the APOL1 renal risk variants. Additionally, HIV-positive individuals face adverse consequences beyond HIV itself, including traditional risk factors for CKD and nephrotoxic effects of antiretroviral therapy. Concerns for nephrotoxicity also extend to HIV-negative individuals using tenofovir disoproxil fumarate-based pre-exposure prophylaxis for the prevention of HIV infection. Therefore, CKD remains an important comorbid condition in the HIV-positive population and an emerging concern among HIV-negative persons receiving pre-exposure prophylaxis. With the improved longevity of HIV-positive individuals, a kidney transplant has become a viable option for many who have progressed to ESRD. Herein, we review the growing knowledge regarding the APOL1 renal risk variants in the context of HIV infection, antiretroviral therapy-related nephrotoxicity, and developments in kidney transplantation among HIV-positive individuals.
| S-EPMC5661296 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-05-27 | GSE205060 | GEO
Project description:Genetic interpretation of rare variants associated with arrhythmogenic cardiomyopathy (ACM) is essential due to their diagnostic implications. New data may relabel previous variant classifications, but how often reanalysis is necessary remains undefined. Five years ago, 39 rare ACM-related variants were identified in patients with features of cardiomyopathy. These variants were classified following the American College of Medical Genetics and Genomics' guidelines. In the present study, we reevaluated these rare variants including novel available data. All cases carried one rare variant classified as being of ambiguous significance (82.05%) or likely pathogenic (17.95%) in 2016. In our comprehensive reanalysis, the classification of 30.77% of these variants changed, mainly due to updated global frequencies. As in 2016, nowadays most variants were classified as having an uncertain role (64.1%), but the proportion of variants with an uncertain role was significantly decreased (17.95%). The percentage of rare variants classified as potentially deleterious increased from 17.95% to 23.07%. Moreover, 83.33% of reclassified variants gained certainty. We propose that periodic genetic reanalysis of all rare variants associated with arrhythmogenic cardiomyopathy should be undertaken at least once every five years. Defining the roles of rare variants may help clinicians obtain a definite diagnosis.
| S-EPMC7996798 | biostudies-literature
Project description:Myeloma cast nephropathy is an obstructing disorder of renal tubules, caused by precipitation of Bence Jones proteins. Myeloma-like cast nephropathy (MLCN) has been reported in the literature to occur in various primary renal and nonrenal diseases. We present a series of three rare cases of cast nephropathy, two of which are HIV patients, and the third patient is receiving cisplatin-based chemotherapy. However, in all three patients plasma cell dyscrasia has been ruled out. A 30-year-old male was admitted to the hospital with facial cellulitis. The second patient is a 31-year-old male who presented with Pneumocystis jiroveci pneumonia. The third patient was treated with cisplatin-based chemotherapy for carcinoma. First two cases revealed foci of diffuse tubular dilatation containing hyaline casts and interstitial inflammatory infiltrate, in addition to globally sclerotic glomeruli with ultrastructural foot process fusion and mesangium expansion. The third case showed acute tubular injury and cast formation of irregular casts composed of amorphous or granular material of low density admixed with scattered high electron-dense globules. Myeloma-like cast nephropathy and true myeloma cast nephropathy pose similar destructive effects on renal parenchyma. This new pattern of HIV-related nephropathy should be considered in HIV patients with MLCN, once monoclonal gammopathy is ruled out.
| S-EPMC5523540 | biostudies-other