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Pediatric Nephrology (Berlin, Germany) Aug 2021HIV-associated nephropathy (HIVAN) predominantly affects people of African ancestry living with HIV who do not receive appropriate antiretroviral therapy (ART).... (Review)
Review
HIV-associated nephropathy (HIVAN) predominantly affects people of African ancestry living with HIV who do not receive appropriate antiretroviral therapy (ART). Childhood HIVAN is characterized by heavy proteinuria and decreased kidney function. Kidney histology shows mesangial expansion, classic or collapsing glomerulosclerosis, and microcystic renal tubular dilatation leading to kidney enlargement. The pathogenesis of HIVAN involves the kidney recruitment of inflammatory cells and the infection of kidney epithelial cells. In addition, both viral and genetic factors play key roles in this disease. Modern ART has improved the outcome and decreased the prevalence of childhood HIVAN. However, physicians have had modest success providing chronic ART to children and adolescents, and we continue to see children with HIVAN all over the world. This article discusses the progress made during the last decade in our understanding of the pathogenesis and treatment of childhood HIVAN, placing particular emphasis on the mechanisms that mediate the infection of kidney epithelial cells, and the roles of cytokines, the HIV-Tat gene, and the Apolipoprotein-1 (APOL1) gene risk variants in this disease. In view of the large number of children living with HIV at risk of developing HIVAN, better prevention and treatment programs are needed to eradicate this disease.
Topics: AIDS-Associated Nephropathy; Adolescent; Apolipoprotein L1; HIV Infections; HIV-1; Humans; Kidney
PubMed: 33044676
DOI: 10.1007/s00467-020-04756-4 -
Transplantation Jul 2021HIV-positive patients had been successfully transplanted for the last 15 y and the donor pool had successfully been expanded to also include HIV-positive donors. (Review)
Review
BACKGROUND
HIV-positive patients had been successfully transplanted for the last 15 y and the donor pool had successfully been expanded to also include HIV-positive donors.
METHODS
We aimed to evaluate the effectiveness of transplantation in HIV-positive patients and highlight some of the important issues reported in the literature. We pooled clinical data from different cohorts to show some of the common issues encountered in HIV-positive transplantation. Furthermore, we searched MEDLINE via PubMed, EMBASE, Cochrane CENTRAL to create a comprehensive table for current evidence for different issues currently encountered when transplanting HIV-positive patients.
RESULTS
We included data from 19 cohort studies and reported on outcomes of the current HIV-positive transplant programs. We made recommendations based on personal experience as well as the experience reported in the literature regarding rejection, opportunistic infection, and HIV-associated nephropathy. Opportunistic infections and malignancies are not a major problem for this population group.
CONCLUSIONS
HIV-positive patients encounter very specific issues after transplantation, specifically related to drug interactions and higher rejection rates. When utilizing HIV-positive donors, the recurrence of HIV-associated nephropathy in the graft kidney is an issue which can be important. Despite some issues with high rejection rates, HIV-positive patients have similar results to HIV-negative patients posttransplantation.
Topics: AIDS-Associated Nephropathy; Anti-HIV Agents; Drug Interactions; Graft Rejection; HIV Infections; Humans; Immunosuppressive Agents; Kidney Transplantation; Recurrence; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 33044431
DOI: 10.1097/TP.0000000000003485 -
Journal of Infection in Developing... Sep 2020End-stage renal disease (ESRD) related to HIV is becoming a leading cause of renal replacement therapy requirement is some areas of the world. Our study aims to describe...
INTRODUCTION
End-stage renal disease (ESRD) related to HIV is becoming a leading cause of renal replacement therapy requirement is some areas of the world. Our study aims to describe the incidence and renal outcomes of HIV-associated nephropathy (HIVAN), and immune-mediated kidney disease related to HIV (HIVICK) in Colombia.
METHODOLOGY
A retrospective cohort study was performed, including all HIVAN or HIVICK incident cases assessed by the infectious diseases division in a high complexity institution in Colombia, between 2004 and 2018. A longitudinal data model under the Generalized Estimating Equations (GEE) method was used to determine changes on the glomerular filtration rate (GFR) over time.
RESULTS
Within a cohort composed by 1509 HIV-infected patients, we identified 22 with HIV-associated glomerular disease. Cumulative incidence was 1.45%. At diagnosis, GFR was above 30 mL/min in 90.8% of patients, and 77.2% displayed sub-nephrotic proteinuria. Factors associated with GFR at diagnosis were: level of CD4 (Coefficient 0.113, CI 95 %: 0.046, 0.179, p < 0.01), and the inverse of the CD4/CD8 ratio. The GEE model did not demonstrate significant changes in the GFR over a 3-year period. Findings were similar when comparing GFR at diagnosis with GFR at 12 (-3.9 mL/min/1.73m2, CI 95% -7.3, 0.4, p = 0.98), 24 (-2.47 mL/min/1.73m2, CI 95% -7.0, 2.1, p=0.85), and 36 months (0.39 mL/min/1.73m2, CI 95% -4.4, 5.2, p = 0.43) of follow-up.
CONCLUSIONS
Patients with glomerular disease associated with HIV have stable GFR over a 3-year period, and low rates of progression towards dialysis requirement. Differences with previous reports could be related with early diagnosis and treatment with highly active antiretroviral therapy.
Topics: AIDS-Associated Nephropathy; Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-CD8 Ratio; Colombia; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; HIV Infections; HIV-1; Humans; Kidney Failure, Chronic; Longitudinal Studies; Male; Middle Aged; Retrospective Studies
PubMed: 33031092
DOI: 10.3855/jidc.12030 -
Disease Models & Mechanisms Oct 2020Modern antiretroviral therapies (ART) have decreased the prevalence of HIV-associated nephropathy (HIVAN). Nonetheless, we continue to see children and adolescents with...
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 () 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-). rAd- and control vectors (2×10) were expressed in the kidney of newborn wild-type and HIV-transgenic (Tg) FVB/N mice without significant proteinuria (=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-Tg mice, and precipitated HIVAN in the first month of life. No significant renal changes were detected in wild-type mice infected with rAd- 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.
Topics: AIDS-Associated Nephropathy; Albuminuria; Amino Acid Sequence; Animals; Animals, Newborn; Apoptosis; Cell Dedifferentiation; Cell Proliferation; Child; Disease Models, Animal; Fibroblast Growth Factor 2; HIV-1; Humans; Kidney; Mice, Transgenic; Podocytes; RNA, Messenger; Vascular Endothelial Growth Factor A; beta-Galactosidase; env Gene Products, Human Immunodeficiency Virus; tat Gene Products, Human Immunodeficiency Virus
PubMed: 32917744
DOI: 10.1242/dmm.045641 -
American Journal of Nephrology 2020Impaired mobility is associated with functional dependence, frailty, and mortality in prevalent patients undergoing dialysis. We investigated risk factors for mobility... (Observational Study)
Observational Study
BACKGROUND
Impaired mobility is associated with functional dependence, frailty, and mortality in prevalent patients undergoing dialysis. We investigated risk factors for mobility impairment, (poor gait speed) in patients incident to dialysis, and changes in gait speed over time in a 2-year longitudinal study.
METHODS
One hundred eighty-three patients enrolled within 6 months of dialysis initiation were followed up 6, 12, and 24 months later. Grip strength, health-related quality of life, and comorbidities were assessed at baseline. Outcomes were (a) baseline gait speed and (b) change in gait speed over time. Gait speed was assessed by 4-meter walk. Multivariate linear regression was used to identify risk factors for low gait speed at baseline. For longitudinal analyses, linear mixed effects modeling with gait speed modeled over time was used as the outcome.
RESULTS
Participants were 54.7 ± 12.8 years old, 52.5% men, 73.9% black with mean dialysis vintage of 100.1 ± 46.9 days and median gait speed 0.78 (0.64-0.094) m/s. Lower health utility and grip strength, diabetic nephropathy, and walking aids were associated with lower baseline gait speed. Loss of 0.1 m/s gait speed occurred in 24% of subjects at 1 year. In multivariate mixed effects models, only age, walking aid use, lower health utility, and lower handgrip strength were significantly associated with gait speed loss.
CONCLUSIONS
In our cohort of incident dialysis patients, overall gait speed is very low and 54.2% of the subjects continue to lose gait speed over 2 years. Older age, lower handgrip strength, and quality of life are risk factors for slowness. Patients at highest risk of poor gait speed can be identified at dialysis initiation to allow targeted implementation of therapeutic options.
Topics: Adult; Age Factors; Aged; Disease Progression; Female; Follow-Up Studies; Frailty; Hand Strength; Humans; Longitudinal Studies; Male; Middle Aged; Quality of Life; Renal Dialysis; Renal Insufficiency, Chronic; Risk Factors; Walking Speed
PubMed: 32781443
DOI: 10.1159/000509225 -
Nature Reviews. Nephrology Oct 2020Reports of collapsing glomerulopathy in patients of African ancestry and high-risk genotype infected with SARS-CoV-2 have emerged during the COVID-19 pandemic. This new... (Review)
Review
Reports of collapsing glomerulopathy in patients of African ancestry and high-risk genotype infected with SARS-CoV-2 have emerged during the COVID-19 pandemic. This new entity, which we term COVID-19-associated nephropathy (COVAN), may particularly impact individuals in some regions of the world. Awareness of this potentially ominous complication of COVID-19 must be raised.
Topics: AIDS-Associated Nephropathy; Apolipoprotein L1; Betacoronavirus; COVID-19; Coronavirus Infections; DNA; Global Health; Humans; Incidence; Pandemics; Pneumonia, Viral; Polymorphism, Single Nucleotide; SARS-CoV-2
PubMed: 32753739
DOI: 10.1038/s41581-020-0332-3 -
AIDS (London, England) Sep 2020HIV-1 can infect and persist in different organs and tissues, resulting in the generation of multiple viral compartments and reservoirs. Increasing evidence supports the...
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.
Topics: AIDS-Associated Nephropathy; CD4-Positive T-Lymphocytes; Cell Proliferation; Epithelial Cells; HIV Infections; Humans; Kidney; Kidney Tubules; Macrophages; Retrospective Studies; Virus Latency; Virus Replication
PubMed: 32701578
DOI: 10.1097/QAD.0000000000002589 -
JCI Insight Sep 2020We 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...
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-β-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.
Topics: AIDS-Associated Nephropathy; Animals; Fibrosis; Humans; Kidney Tubules; Loss of Function Mutation; Mice; Mice, Inbred C57BL; Protein Serine-Threonine Kinases; Renal Insufficiency, Chronic; Smad3 Protein; Transforming Growth Factor beta
PubMed: 32701510
DOI: 10.1172/jci.insight.136004 -
American Journal of Physiology. Renal... Aug 2020Human immunodeficiency virus (HIV) infection of kidney cells can lead to HIV-associated nephropathy (HIVAN) and aggravate the progression of other chronic kidney...
Human immunodeficiency virus (HIV) infection of kidney cells can lead to HIV-associated nephropathy (HIVAN) and aggravate the progression of other chronic kidney diseases. Thus, a better understanding of the mechanisms of HIV-induced kidney cell injury is needed for effective therapy against HIV-induced kidney disease progression. We have previously shown that the acetylation and activation of key inflammatory regulators, NF-κB p65 and STAT3, were increased in HIVAN kidneys. Here, we demonstrate the key role of sirtuin 1 (SIRT1) deacetylase in the regulation of NF-κB and STAT3 activity in HIVAN. We found that SIRT1 expression was reduced in the glomeruli of human and mouse HIVAN kidneys and that HIV-1 gene expression was associated with reduced SIRT1 expression and increased acetylation of NF-κB p65 and STAT3 in cultured podocytes. Interestingly, SIRT1 overexpression, in turn, reduced the expression of negative regulatory factor in podocytes stably expressing HIV-1 proviral genes, which was associated with inactivation of NF-κB p65 and a reduction in HIV-1 long terminal repeat promoter activity. In vivo, the administration of the small-molecule SIRT1 agonist BF175 or inducible overexpression of SIRT1 specifically in podocytes markedly attenuated albuminuria, kidney lesions, and expression of inflammatory markers in Tg26 mice. Finally, we showed that the reduction in SIRT1 expression by HIV-1 is in part mediated through miR-34a expression. Together, our data provide a new mechanism of SIRT1 regulation and its downstream effects in HIV-1-infected kidney cells and indicate that SIRT1/miR-34a are potential drug targets to treat HIV-related kidney disease.
Topics: AIDS-Associated Nephropathy; Animals; Humans; Kidney; Kidney Glomerulus; Mice; Podocytes; Renal Insufficiency, Chronic; Sirtuin 1; Transcription Factor RelA
PubMed: 32657157
DOI: 10.1152/ajprenal.00140.2020 -
Clinical Journal of the American... Feb 2021Rates of many types of severe kidney disease are much higher in Black individuals than most other ethnic groups. Much of this disparity can now be attributed to genetic... (Review)
Review
Rates of many types of severe kidney disease are much higher in Black individuals than most other ethnic groups. Much of this disparity can now be attributed to genetic variants in the apoL1 (APOL1) gene found only in individuals with recent African ancestry. These variants greatly increase rates of hypertension-associated ESKD, FSGS, HIV-associated nephropathy, and other forms of nondiabetic kidney disease. We discuss the population genetics of APOL1 risk variants and the clinical spectrum of APOL1 nephropathy. We then consider clinical issues that arise for the practicing nephrologist caring for the patient who may have APOL1 kidney disease.
Topics: AIDS-Associated Nephropathy; Africa; Alleles; Apolipoprotein L1; Black People; Diabetic Nephropathies; Genetic Variation; Glomerulosclerosis, Focal Segmental; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Risk Factors
PubMed: 32616495
DOI: 10.2215/CJN.15161219