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BioRxiv : the Preprint Server For... Nov 2023Hyponatremia and salt wasting is a common occurance in patients with HIV/AIDS, however, the understanding of its contributing factors is limited. HIV viral protein R...
Hyponatremia and salt wasting is a common occurance in patients with HIV/AIDS, however, the understanding of its contributing factors is limited. HIV viral protein R (Vpr) contributes to HIV-associated nephropathy. To investigate the effects of Vpr on the expression level of the gene, encoding the Na-Cl cotransporter, which is responsible for sodium reabsorption in distal nephron segments, we performed single-nucleus RNA sequencing of kidney cortices from three wild-type (WT) and three Vpr-transgenic (Vpr Tg) mice. The results showed that the percentage of distal convoluted tubule (DCT) cells was significantly lower in Vpr Tg mice compared with WT mice (P < 0.05), and that in Vpr Tg mice, expression was not different in DCT cell cluster. The DCT1 subcluster had fewer cells in Vpr Tg mice compared with WT (P < 0.01). Immunohistochemistry demonstrated fewer DCT1 segments in Vpr Tg mice. Differential gene expression analysis comparing Vpr Tg and WT in the DCT cluster showed , an inhibitor of apoptosis, to be the most downregulated gene. These observations demonstrate that the salt-wasting effect of Vpr in Vpr Tg mice is mediated by loss of DCT1 segments via apoptosis dysregulation.
PubMed: 36945458
DOI: 10.1101/2023.02.02.526686 -
Retrovirology Mar 2023Although 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... (Review)
Review
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.
Topics: Animals; Humans; HIV Infections; HIV-1; Animals, Genetically Modified; AIDS-Associated Nephropathy; Epithelial Cells
PubMed: 36927552
DOI: 10.1186/s12977-023-00617-8 -
Annals of Hematology May 2023Chronic kidney disease (CKD) has a significant impact on sickle cell disease (SCD) morbidity and mortality. Early identification of individuals at highest risk of...
Chronic kidney disease (CKD) has a significant impact on sickle cell disease (SCD) morbidity and mortality. Early identification of individuals at highest risk of developing CKD may allow therapeutic intervention to prevent worse outcomes. This study aimed to evaluate the prevalence and risk factors for reduced estimated glomerular filtration rate (eGFR) among adults with SCD in Brazil. Participants in the REDS-III multicenter SCD cohort with more severe genotypes aged ≥ 18 years with at least two serum creatinine values were analyzed. The eGFR was calculated using the Jamaica Sickle Cell Cohort Study GFR equation. The eGFR categories were defined according to the K/DOQI. Participants with eGFR ≥ 90 were compared to those with those with eGFR < 90. Among the 870 participants, 647 (74.4%) had eGFR ≥ 90, 211 (24.3%) had eGFR 60 to 89, six (0.7%) had eGFR 30 to 59, and six (0.7%) had ESRD. Male sex (OR: 37.3; 95%CI: 22.4-65.1), higher age (OR: 1.04; 95%CI: 1.02-1.06), higher diastolic blood pressure (OR: 1.03; 95%CI: 1.009-1.06), lower Hb (OR: 0.80; 95%CI: 0.68-0.93), and lower reticulocytes (OR: 0.94; 95%CI: 0.89-0.99) levels were independently associated with eGFR < 90. There was a trend towards higher odds of death in participants with eGFR < 90 (OR: 1.8; 95%CI: 0.95-3.32; p = 0.065). In turn, participants with eGFR < 60 had a 12.2 (95%CI: 2.1-96.9) times higher odds for death when compared to those with eGFR ≥ 60. In this study, eGFR < 90 was observed in one-quarter of adults. Older age, male sex, higher diastolic blood pressure, lower hemoglobin, and lower reticulocyte levels were associated with occurrence of eGFR < 90. Estimated GFR < 60 increased the risk of mortality.
Topics: Humans; Adult; Male; Brazil; Cohort Studies; Glomerular Filtration Rate; Anemia, Sickle Cell; Renal Insufficiency, Chronic; Creatinine
PubMed: 36884065
DOI: 10.1007/s00277-023-05150-4 -
The American Journal of Pathology Jun 2023HIV-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...
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.
Topics: Mice; Humans; Animals; Protein-Tyrosine Kinases; AIDS-Associated Nephropathy; Mice, Transgenic; HIV Infections; Tyrosine; src-Family Kinases; Proto-Oncogene Proteins c-hck
PubMed: 36868467
DOI: 10.1016/j.ajpath.2023.02.006 -
Current Opinion in HIV and AIDS Mar 2023To highlight advances in understanding of host factors, in particular host genetics, in the development of chronic kidney disease (CKD) in people with HIV. (Review)
Review
PURPOSE OF REVIEW
To highlight advances in understanding of host factors, in particular host genetics, in the development of chronic kidney disease (CKD) in people with HIV.
RECENT FINDINGS
In Black populations, the G1 and G2 variants of the apolipoprotein L1 (APOL1) gene predispose to HIV-associated nephropathy (HIVAN). The risk of HIVAN is mostly confined to individuals with two APOL1 variants (kidney-risk genotypes). APOL1 kidney-risk genotypes are present in approximately 80% of patients with HIVAN and account for nearly half the burden of end-stage CKD in people of African ancestry with HIV. Progress has been made in elucidating the mechanisms of kidney injury in APOL1 nephropathy, and several targeted molecular therapies are being investigated in clinical trials. Genome- and epigenome-wide association studies are identifying additional genes and pathways that may be involved in the pathogenesis of CKD in people with HIV.
SUMMARY
Genetic variants of APOL1 are strongly associated with severe CKD and contribute to the high rates of CKD in Black populations with HIV. Most individuals with APOL1 kidney-risk genotypes, however, do not develop kidney disease and further studies are required to understand the role of additional genetic and environmental factors that may affect CKD risk in this population.
Topics: Humans; Apolipoprotein L1; Genotype; HIV Infections; Renal Insufficiency, Chronic; Black People
PubMed: 36722197
DOI: 10.1097/COH.0000000000000784 -
Current HIV/AIDS Reports Apr 2023With the advent of antiretroviral therapy, HIV infection has become a chronic disease in developed countries. (Review)
Review
PURPOSE OF REVIEW
With the advent of antiretroviral therapy, HIV infection has become a chronic disease in developed countries.
RECENT FINDINGS
Non-HIV-driven risk factors for kidney disease, such as APOL1 risk variants and other genetic and environmental factors, have been discovered and are better described. Consequently, the field of HIV-associated kidney disease has evolved with greater attention given to traditional risk factors of CKD and antiretroviral treatment's nephrotoxicity. In this review, we explore risk factors of HIV-associated kidney disease, diagnostic tools, kidney pathology in HIV-positive individuals, and antiretroviral therapy-associated nephrotoxicity.
Topics: Humans; HIV Infections; AIDS-Associated Nephropathy; Kidney Diseases; Risk Factors; Anti-Retroviral Agents; Apolipoprotein L1
PubMed: 36695948
DOI: 10.1007/s11904-023-00645-1 -
Medicina (Kaunas, Lithuania) Dec 2022The Human Immunodeficiency Virus (HIV) is a highly morphic, retrovirus that rapidly evolves through mutation as well as recombination. Because of the immunocompromised...
The Human Immunodeficiency Virus (HIV) is a highly morphic, retrovirus that rapidly evolves through mutation as well as recombination. Because of the immunocompromised status in HIV patients, there is often a higher chance of acquiring different secondary infections followed by liver cirrhosis, hepatitis B & C, and HIV-associated nephropathy. The current study was conducted to see the prevalence of secondary infections, hematological and biochemical markers for liver and renal associated diseases, and to detect the envelope gene (GP41) in newly diagnosed HIV patients. A total of 37 samples were collected from HIV-positive patients registered in different hospital settings under the National AIDS control program. The collected samples were processed for hepatitis B, hepatitis C, hematological analysis, and biochemical analysis. To identify the envelope gene in newly diagnosed HIV patients, polymerase chain reaction (PCR) was performed using four gene-specific primers. The HIV infections were seen more in male as compared to females. A significant decrease in complete blood count was observed in HIV patients when compared to healthy individuals. There was a significant increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine observed in HIV patients. No significant difference was observed in alkaline phosphatase (ALP), total bilirubin, and albumin levels when compared to healthy control. Anemia was observed in 59.4% of HIV patients. A total of three (8.1%) patients were found to be co-infected with hepatitis B and one (2.7 %) was co-infected with hepatitis C. Out of these 37 tested samples, a total of four showed the successful amplification of the envelope gene. This study provides platform for the health care facilitators to regularly monitor the signs, symptoms and clinical biomarkers of HIV-associated infections to prevent toxicity at an early stage to improve the quality of life (QoL) and minimize the mortality rate in HIV patients. Envelope gene mutating frequently results in drug resistance, and thus future research on polymorphism analysis will reveal points of substitutions to improve drug designing.
Topics: Female; Humans; Male; HIV Infections; HIV; Quality of Life; Coinfection; Hepatitis B; Hepatitis C; Hepacivirus; Prevalence; Biomarkers
PubMed: 36676716
DOI: 10.3390/medicina59010093 -
Computational and Structural... 2023Diabetic nephropathy (DN) is one of the most established microvascular complications of diabetes and a key cause of end-stage renal disease. It is well established that...
Diabetic nephropathy (DN) is one of the most established microvascular complications of diabetes and a key cause of end-stage renal disease. It is well established that gene susceptibility to DN plays a critical role in disease pathophysiology. Therefore, many genetic studies have been performed to categorize candidate genes in prominent diabetic cohorts, aiming to investigate DN pathogenesis and etiology. In this study, we performed a meta-analysis on the expression profiles of GSE1009, GSE30122, GSE96804, GSE99340, GSE104948, GSE104954, and GSE111154 to identify critical transcriptional factors associated with DN progression. The analysis was conducted for all individual datasets for each kidney tissue (glomerulus, tubules, and kidney cortex). We identified distinct clusters of susceptibility genes that were dysregulated in a renal compartment-specific pattern. Further, we recognized a small but a closely connected set of these susceptibility genes enriched for podocyte differentiation, several of which were characterized as genes encoding critical transcriptional factors (TFs) involved in DN development and podocyte function. To validate the role of identified TFs in DN progression, we functionally validated the three main TFs (DACH1, LMX1B, and WT1) identified through differential gene expression and network analysis using the hyperglycemic zebrafish model. We report that hyperglycemia-induced altered gene expression of the key TF genes leads to morphological abnormalities in zebrafish glomeruli, pronephric tubules, proximal and distal ducts. This study demonstrated that altered expression of these TF genes could be associated with hyperglycemia-induced nephropathy and, thus, aids in understanding the molecular drivers, essential genes, and pathways that trigger DN initiation and development.
PubMed: 36659918
DOI: 10.1016/j.csbj.2022.12.054 -
Journal of Medical Case Reports Dec 2022We present this case of coronavirus disease 2019-associated acute kidney injury with rhabdomyolysis-with noteworthy renal biopsy findings demonstrating myoglobin cast...
BACKGROUND
We present this case of coronavirus disease 2019-associated acute kidney injury with rhabdomyolysis-with noteworthy renal biopsy findings demonstrating myoglobin cast nephropathy-to add to the limited literature on coronavirus disease 2019-related acute kidney injury and rhabdomyolysis.
CASE PRESENTATION
A 67-year-old Caucasian man presented to our hospital with 3 weeks of malaise and decreased oral intake and several days of abnormal taste, poor appetite, decrease urine output, gastrointestinal symptoms, and myalgias, and was ultimately diagnosed with coronavirus disease 2019. His hospital course was complicated by acute kidney injury and, upon workup of his renal failure, was diagnosed with myoglobin cast nephropathy due to coronavirus disease 2019-mediated rhabdomyolysis. Ultimately, his renal function improved following hydration back to his baseline 6 weeks after his initial diagnosis of coronavirus disease 2019.
CONCLUSIONS
Given our limited knowledge of manifestations of coronavirus disease 2019, it is important to have a more in-depth understanding of the spectrum of disease of coronavirus disease 2019, which can affect various organ systems, including the kidney, and the manifestations of end-organ damage associated with it. We present this case to highlight a rarely reported finding of myoglobin cast nephropathy due to coronavirus disease 2019-mediated rhabdomyolysis.
Topics: Male; Humans; Aged; COVID-19; Myoglobin; Rhabdomyolysis; Acute Kidney Injury; Kidney
PubMed: 36578087
DOI: 10.1186/s13256-022-03721-z -
Kidney International Mar 2023Chronic kidney disease (CKD) is a common cause of morbidity in human immunodeficiency virus (HIV)-positive individuals. HIV infection leads to a wide spectrum of kidney...
Chronic kidney disease (CKD) is a common cause of morbidity in human immunodeficiency virus (HIV)-positive individuals. HIV infection leads to a wide spectrum of kidney cell damage, including tubular epithelial cell (TEC) injury. Among the HIV-1 proteins, the pathologic effects of viral protein R (Vpr) are well established and include DNA damage response, cell cycle arrest, and cell death. Several in vitro studies have unraveled the molecular pathways driving the cytopathic effects of Vpr in tubular epithelial cells. However, the in vivo effects of Vpr on tubular injury and CKD pathogenesis have not been thoroughly investigated. Here, we use a novel inducible tubular epithelial cell-specific Vpr transgenic mouse model to show that Vpr expression leads to progressive tubulointerstitial damage, interstitial inflammation and fibrosis, and tubular cyst development. Importantly, Vpr-expressing tubular epithelial cells displayed significant hypertrophy, aberrant cell division, and atrophy; all reminiscent of tubular injuries observed in human HIV-associated nephropathy (HIVAN). Single-cell RNA sequencing analysis revealed the Vpr-mediated transcriptomic responses in specific tubular subsets and highlighted the potential multifaceted role of p53 in the regulation of cell metabolism, proliferation, and death pathways in Vpr-expressing tubular epithelial cells. Thus, our study demonstrates that HIV Vpr expression in tubular cells is sufficient to induce HIVAN-like tubulointerstitial damage and fibrosis, independent of glomerulosclerosis and proteinuria. Additionally, as this new mouse model develops progressive CKD with diffuse fibrosis and kidney failure, it can serve as a useful tool to examine the mechanisms of kidney disease progression and fibrosis in vivo.
Topics: Animals; Humans; Mice; AIDS-Associated Nephropathy; Disease Models, Animal; Gene Products, vpr; HIV Infections; HIV-1; Human Immunodeficiency Virus Proteins; Mice, Transgenic; Renal Insufficiency, Chronic
PubMed: 36565808
DOI: 10.1016/j.kint.2022.12.012