-
Journal of the American Society of... Jan 2022To gain insight into the pathogenesis of collapsing glomerulopathy, a rare form of FSGS that often arises in the setting of viral infections, we performed a genome-wide...
BACKGROUND
To gain insight into the pathogenesis of collapsing glomerulopathy, a rare form of FSGS that often arises in the setting of viral infections, we performed a genome-wide association study (GWAS) among inbred mouse strains using a murine model of HIV-1 associated nephropathy (HIVAN).
METHODS
We first generated F1 hybrids between HIV-1 transgenic mice on the FVB/NJ background and 20 inbred laboratory strains. Analysis of histology, BUN, and urinary NGAL demonstrated marked phenotypic variation among the transgenic F1 hybrids, providing strong evidence for host genetic factors in the predisposition to nephropathy. A GWAS in 365 transgenic F1 hybrids generated from these 20 inbred strains was performed.
RESULTS
We identified a genome-wide significant locus on chromosome 13-C3 and multiple additional suggestive loci. Crossannotation of the Chr. 13 locus, including single-cell transcriptomic analysis of wildtype and HIV-1 transgenic mouse kidneys, nominated as the most likely candidate gene. is highly expressed in podocytes, encodes a transcriptional cofactor that interacts with LDB1 and LMX1B, which are both previously implicated in FSGS. Consistent with these data, older null mice spontaneously develop glomerulosclerosis, tubular casts, interstitial fibrosis, and inflammation, similar to the HIVAN mouse model.
CONCLUSIONS
These findings demonstrate the utility of GWAS in mice to uncover host genetic factors for rare kidney traits and suggest as susceptibility gene for HIVAN, potentially acting the LDB1-LMX1B transcriptional network.
Topics: AIDS-Associated Nephropathy; Animals; DNA-Binding Proteins; Disease Models, Animal; Female; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Glomerulosclerosis, Focal Segmental; Male; Mice; Mice, Transgenic
PubMed: 34893534
DOI: 10.1681/ASN.2021040543 -
Transplant Infectious Disease : An... Oct 2020We report a case of a 50-year-old male with a history of HIV and kidney transplant who presented with SARS-CoV-2. We also present a review of COVID-19 cases in kidney... (Review)
Review
We report a case of a 50-year-old male with a history of HIV and kidney transplant who presented with SARS-CoV-2. We also present a review of COVID-19 cases in kidney transplant recipients.
Topics: AIDS-Associated Nephropathy; Antirheumatic Agents; COVID-19; COVID-19 Nucleic Acid Testing; Graft Rejection; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; RNA, Viral; SARS-CoV-2; Transplant Recipients
PubMed: 32453483
DOI: 10.1111/tid.13338 -
BMC Nephrology Sep 2021HIV subjects have several kidney pathologies, like HIV-associated nephropathy or antiretroviral therapy injury, among others. The global prevalence of Chronic Kidney...
BACKGROUND
HIV subjects have several kidney pathologies, like HIV-associated nephropathy or antiretroviral therapy injury, among others. The global prevalence of Chronic Kidney Disease (CKD) is 8-16%; however, in HIV subjects, the prevalence varies between geographic regions (2-38%). The aim was to determine the prevalence of CKD and identify the associated risk factors.
METHODS
A longitudinal descriptive study was carried out at the 'Hospital Civil de Guadalajara' Feb'18 - Jan'19. Basal clinical, demographic, opportunistic infections (OI), and laboratory data were obtained at months 0 and 3; inclusion criteria were ≥ 18 years old, naïve HIV + , urine albumin/creatinine ratio, serum creatinine & urine test, and signed informed consent. Descriptive and multiple logistic regression statistical analyses were made.
RESULTS
One hundred twenty subjects were included; 92.5% were male, 33 ± 9.5 years, 60% consumed tobacco, 73% alcohol, and 59% some type of drug. The CKD prevalence was 15.8%. CKD patients had a higher risk of hepatitis C virus coinfection, Relative Risk (RR):5.9; HCV infection, RR:4.3; ≥ 30 years old, RR:3.9; C clinical-stage, RR:3.5; CD4 T cells count < 200 cells/μL, RR: 2.4; and HIV-1 viral load ≥ 100,000 cop/mL, RR: 2.7.
CONCLUSIONS
Our study showed a higher CKD prevalence in patients with HIV; higher CKD development with coinfections as Hepatitis C Virus and Mycobacterium tuberculosis. The identification and prompt management of CKD and coinfections should be considered to avoid the progression and to delay renal replacement therapy as long as possible.
Topics: AIDS-Associated Nephropathy; Adult; CD4 Lymphocyte Count; CD4-CD8 Ratio; Coinfection; Female; HIV Seropositivity; HIV-1; Humans; Male; Mexico; Prevalence; Renal Insufficiency, Chronic; Risk Factors; Viral Load
PubMed: 34556049
DOI: 10.1186/s12882-021-02526-4 -
Nephrology, Dialysis, Transplantation :... Feb 2021Chronic kidney disease (CKD) is a common cause of morbidity and mortality in human immunodeficiency virus (HIV)-positive individuals. Among the HIV-related kidney...
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.
Topics: AIDS-Associated Nephropathy; Animals; Disease Models, Animal; Fibrosis; Inflammation; MAP Kinase Kinase Kinase 5; Mice; Mice, Transgenic; Protein Kinase Inhibitors; Proteinuria
PubMed: 33097961
DOI: 10.1093/ndt/gfaa198 -
Journal of Vascular Surgery Dec 2020Despite improvements in treating human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS), the risk of end-stage renal disease and need...
OBJECTIVE
Despite improvements in treating human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS), the risk of end-stage renal disease and need for long-term arteriovenous (AV) access for hemodialysis remain high in HIV-infected patients. Associations of HIV/AIDS with AV access creation complications have been conflicting. Our goal was to clarify short- and long-term outcomes of patients with HIV/AIDS undergoing AV access creation.
METHODS
The Vascular Quality Initiative registry was queried from 2011 to 2018 for all patients undergoing AV access creation. Documentation of HIV infection status with or without AIDS was recorded. Data were propensity score matched (4:1) between non-HIV-infected patients and HIV/AIDS patients. Subsequent multivariable analysis and Kaplan-Meier analysis were performed for short- and long-term outcomes.
RESULTS
There were 25,711 upper extremity AV access creations identified: 25,186 without HIV infection (98%), 424 (1.6%) with HIV infection, and 101 (.4%) with AIDS. Mean age was 61.8 years, and 55.8% were male. Patients with HIV/AIDS were more often younger, male, nonwhite, nonobese, and current smokers; they were more often on Medicaid and more likely to have a history of intravenous drug use, and they were less often diabetic and less likely to have cardiac comorbidities (P < .05 for all). There was no significant difference in autogenous or prosthetic access used in these cohorts. Wound infection requiring incision and drainage or explantation within 90 days was low for all groups (0.6% vs 1.9 vs 0%; P = .11) of non-HIV-infected patients vs HIV-infected patients vs AIDS patients. Kaplan-Meier analysis showed no significant difference in 1-year freedom from primary patency loss (43.9% vs 46.3%; P =.6), 1-year freedom from reintervention (61% vs 60.7%,; P = .81), or 3-year survival (83% vs 83.8%; P = .57) for those with and without HIV/AIDS, respectively. Multivariable analysis demonstrated that patients with HIV/AIDS were not at significantly higher risk for access reintervention (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.76-1.24; P = .81), occlusion (HR, 1.06; 95% CI, 0.86-1.29; P = .6), or mortality (HR, 1.08; 95% CI, 0.83-1.43; P = .57).
CONCLUSIONS
Patients with HIV/AIDS undergoing AV access creation have outcomes similar to those of patients without HIV infection, including long-term survival. Patients with HIV/AIDS had fewer traditional end-stage renal disease risk factors compared with non-HIV-infected patients. Our findings show that the contemporary approach for creation and management of AV access in patients with HIV/AIDS should be continued; however, further research is needed to identify risk factors in this population.
Topics: AIDS-Associated Nephropathy; Adult; Aged; Arteriovenous Shunt, Surgical; Female; HIV Infections; Humans; Kidney Failure, Chronic; Male; Middle Aged; Postoperative Complications; Registries; Renal Dialysis; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; United States; Upper Extremity; Vascular Patency
PubMed: 32276018
DOI: 10.1016/j.jvs.2020.03.030 -
Clinical Journal of the American... Feb 2016Prior studies have shown that the APOL1 risk alleles are associated with a greater risk of HIV-associated nephropathy and FSGS among blacks who are HIV positive. We...
BACKGROUND AND OBJECTIVES
Prior studies have shown that the APOL1 risk alleles are associated with a greater risk of HIV-associated nephropathy and FSGS among blacks who are HIV positive. We sought to determine whether the APOL1 high-risk genotype incrementally improved the prediction of these underlying lesions beyond conventional clinical factors.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
In a cross-sectional study, we analyzed data from 203 blacks who are HIV positive, underwent kidney biopsies between 1996 and 2011, and were genotyped for the APOL1 G1 and G2 alleles. Predictive logistic regression models with conventional clinical factors were compared with those that also included APOL1 genotype using receiver-operating curves and bootstrapping analyses with crossvalidation.
RESULTS
The addition of APOL1 genotype to HIV-related risk factors for kidney disease in a predictive model improved the prediction of non-HIV-associated nephropathy FSGS, specifically, increasing the c statistic from 0.65 to 0.74 (P=0.04). Although two risk alleles were significantly associated with higher odds of HIV-associated nephropathy, APOL1 genotype did not add incrementally to the prediction of this specific histopathology.
CONCLUSIONS
APOL1 genotype may provide additional diagnostic information to traditional clinical variables in predicting underlying FSGS spectrum lesions in blacks who are HIV positive. In contrast, although APOL1 risk genotype predicts HIV-associated nephropathy, it lacked a high c statistic sufficient for discrimination to eliminate the role of kidney biopsy in the clinical care of blacks who are HIV positive with nephrotic proteinuria or unexplained kidney disease.
Topics: AIDS-Associated Nephropathy; Adult; Black or African American; Apolipoprotein L1; Apolipoproteins; Biopsy; Chi-Square Distribution; Cross-Sectional Studies; Female; Genetic Predisposition to Disease; Glomerulosclerosis, Focal Segmental; HIV Infections; Humans; Kidney; Lipoproteins, HDL; Logistic Models; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Phenotype; Predictive Value of Tests; Retrospective Studies; Risk Assessment; Risk Factors
PubMed: 26668025
DOI: 10.2215/CJN.07490715 -
Journal of Infection and Public Health Nov 2023Despite the rising number of people living with human immunodeficiency virus (HIV), there is a lack of knowledge about the factors that lead to PLWHs being hospitalized...
BACKGROUND
Despite the rising number of people living with human immunodeficiency virus (HIV), there is a lack of knowledge about the factors that lead to PLWHs being hospitalized in worldwide literature. Our study aimed to investigate PLWH admissions in Sicily (Italy) between January 2010 and September 2021 and to analyze the characteristics and risk factors for in-hospital mortality and differences between Italians and foreigners.
METHODS
Data from the hospital discharge forms of all people living with HIV (PLWH) hospitalized in Sicilian hospitals were retrospectively collected. Age, sex, nationality, length of stay, acquired immunodeficiency syndrome (AIDS), and non-AIDS-related diseases were evaluated using univariate analysis according to in-hospital mortality rates. The factors associated with mortality were included in the logistic regression model.
RESULTS
In total, 5281 admissions from 2726 PLWHs occurred, most of which were related to non-AIDS diseases. Approximately 20 % regarded foreign patients, mainly from Africa. Logistic regression analysis revealed an association between in-hospital mortality and some AIDS- and non-AIDS-related diseases (wasting syndrome, lymphomas, Kaposi sarcomas, progressive multifocal leukoencephalopathy, cryptococcosis, abscesses, sepsis, cardiovascular disease, nephropathy, and respiratory diseases). African patient admissions were significantly associated with tuberculosis, toxoplasmosis, Burkitt lymphoma, and hepatitis B diagnoses.
CONCLUSIONS
Our study showed that most hospitalizations were related to non-AIDS-defining diseases, with differences between Italian and foreign patients, mainly from Africa.
PubMed: 37729685
DOI: 10.1016/j.jiph.2023.08.023 -
JCI Insight Nov 2018Our previous work demonstrated a protective role of protein S in early diabetic kidney disease (DKD). Protein S exerts antiinflammatory and antiapoptotic effects through...
Our previous work demonstrated a protective role of protein S in early diabetic kidney disease (DKD). Protein S exerts antiinflammatory and antiapoptotic effects through the activation of TYRO3, AXL, and MER (TAM) receptors. Among the 3 TAM receptors, we showed that the biological effects of protein S were mediated largely by TYRO3 in diabetic kidneys. Our data now show that TYRO3 mRNA expression is highly enriched in human glomeruli and that TYRO3 protein is expressed in podocytes. Interestingly, glomerular TYRO3 mRNA expression increased in mild DKD but was suppressed in progressive DKD, as well as in focal segmental glomerulosclerosis (FSGS). Functionally, morpholino-mediated knockdown of tyro3 altered glomerular filtration barrier development in zebrafish larvae, and genetic ablation of Tyro3 in murine models of DKD and Adriamycin-induced nephropathy (ADRN) worsened albuminuria and glomerular injury. Conversely, the induction of TYRO3 overexpression specifically in podocytes significantly attenuated albuminuria and kidney injury in mice with DKD, ADRN, and HIV-associated nephropathy (HIVAN). Mechanistically, TYRO3 expression was suppressed by activation of TNF-α/NF-κB pathway, which may contribute to decreased TYRO3 expression in progressive DKD and FSGS, and TYRO3 signaling conferred antiapoptotic effects through the activation of AKT in podocytes. In conclusion, TYRO3 plays a critical role in maintaining normal podocyte function and may be a potential new drug target to treat glomerular diseases.
Topics: AIDS-Associated Nephropathy; Adult; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Doxorubicin; Gene Knockdown Techniques; Humans; Kidney Glomerulus; Male; Mice; Mice, Inbred C57BL; Podocytes; Protective Factors; Receptor Protein-Tyrosine Kinases; Transcriptional Activation; Zebrafish
PubMed: 30429374
DOI: 10.1172/jci.insight.123482 -
Frontiers in Immunology 2019Apolipoprotein L1 (APOL1) has broad innate immune functions and has been shown to restrict HIV replication by multiple mechanisms. Coding variants in are strongly...
Apolipoprotein L1 (APOL1) has broad innate immune functions and has been shown to restrict HIV replication by multiple mechanisms. Coding variants in are strongly associated with HIV-associated nephropathy (HIVAN) in persons with untreated HIV infection; however, the mechanism by which variant protein potentiates renal injury in the presence of high viral load is not resolved. Little is known about the association of genotypes with HIV viral load, HIV acquisition, or progression to AIDS. We assessed the role of coding variants on HIV-1 acquisition using the conditional logistic regression test, on viral load using the test or ANOVA, and on progression to AIDS using Cox proportional hazards models among African Americans enrolled in the ALIVE HIV natural history cohort ( = 775). variants were not associated with susceptibility to HIV-1 acquisition by comparing genotype frequencies between HIV-1 positive and exposed or at-risk HIV-1 uninfected groups (recessive model, 12.8 vs. 12.5%, respectively; OR 1.02, 95% CI 0.62-1.70). Similar null results were observed for dominant and additive models. variants were not associated with HIV-1 viral load or with risk of progression to AIDS [Relative hazards (RH) 1.33, 95% CI 0.30-5.89 and 0.96, 95% CI 0.49-1.88, for recessive and additive models, respectively]. In summary, we found no evidence that variants are associated with host susceptibility to HIV-1 acquisition, set-point HIV-1 viral load or time to incident AIDS. These results suggest that APOL1 variants are unlikely to influence HIV infection or progression among individuals of African ancestry.
Topics: Adult; Alleles; Apolipoprotein L1; CD4 Lymphocyte Count; Disease Progression; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Genotype; HIV Infections; HIV-1; Haplotypes; Host-Pathogen Interactions; Humans; Middle Aged; Viral Load
PubMed: 30733721
DOI: 10.3389/fimmu.2019.00053 -
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