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Journal of Nephrology May 2023The risk of various types of kidney disease is significantly increased in the presence of APOL1 high-risk genotype (carriage of two risk alleles), particularly... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The risk of various types of kidney disease is significantly increased in the presence of APOL1 high-risk genotype (carriage of two risk alleles), particularly HIV-associated nephropathy (HIVAN). However, there are discrepancies in the existing evidence about the level of association between APOL1 high-risk genotype and the risk of kidney diseases in people living with HIV (PLWHIV).
METHODS
This systematic review and meta-analysis was conducted to assess the relationship between the APOL1 genotypes and kidney disease in the HIV population. An a priori protocol registered on PROSPERO (ID: CRD42021253877), was followed by a systematic search of five electronic databases. Database-specific search terms were used to identify observational studies that evaluated the outcomes chosen in the review, based on a set of prespecified eligibility criteria. Using a random effect model, the odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were pooled for the meta-analysis.
RESULTS
After screening 4418 citations, 14 articles comprising 11,069 participants were included in this review. The risk of chronic kidney disease (CKD) in the HIV positive population was significantly increased in the presence of two APOL1 risk alleles (OR 4.65 [95% CI 3.51-6.15]). Also, a significant association was observed between the carriage of two risk APOL1 variants and proteinuria (OR 2.58 [95% CI 2.05-3.25]), HIVAN (OR 16.67 [95% CI 10.22-27.19]), and progression to end-stage kidney disease (ESKD) hazard ratio: 1.79 (95% CI 1.20-2.66).
CONCLUSION
This review highlights a strong association between the presence of two risk APOL1 variants and an increased risk of kidney disease in PLWHIV, and provides a more precise estimate of the effect size, with smaller 95% CIs for CKD, HIVAN, and progression to ESKD.
Topics: Humans; Apolipoprotein L1; Apolipoproteins; AIDS-Associated Nephropathy; Genotype; Kidney Failure, Chronic; Renal Insufficiency, Chronic
PubMed: 36510118
DOI: 10.1007/s40620-022-01512-9 -
Pediatric Nephrology (Berlin, Germany) Aug 2023HIV infection remains one of the leading causes of morbidity and mortality worldwide, especially in children living in resource-limited settings. Although the World... (Review)
Review
HIV infection remains one of the leading causes of morbidity and mortality worldwide, especially in children living in resource-limited settings. Although the World Health Organization (WHO) recently recommended antiretroviral therapy (ART) initiation upon diagnosis regardless of the number of CD4, ART access remains limited, especially in children living in sub-Saharan Africa (SSA). HIV-infected children who do not receive appropriate ART are at increased risk of developing HIV-associated nephropathy (HIVAN). Although due to genetic susceptibility, SSA is recognized to be the epicenter of HIVAN, limited information is available regarding the burden of HIVAN in children living in Africa. The present review discusses the information available to date on the prevalence, pathogenesis, risk factors, diagnosis, and management of HIVAN in children, focusing on related challenges in a resource-limited setting.
Topics: Humans; Child; AIDS-Associated Nephropathy; HIV Infections; Resource-Limited Settings; Risk Factors; Africa South of the Sahara
PubMed: 36472655
DOI: 10.1007/s00467-022-05819-4 -
BMJ Case Reports Oct 2022Preliminary data on HIV-positive donor to HIV-positive recipient kidney transplantation suggest promising patient outcomes without adverse events. This is an important...
Preliminary data on HIV-positive donor to HIV-positive recipient kidney transplantation suggest promising patient outcomes without adverse events. This is an important step in expanding the donor pool and opportunity for transplantation in HIV-positive patients.We herein report the first case of HIV-positive donor to HIV-positive recipient kidney transplantation in Denmark. Our patient has demonstrated a successful post-transplant course with excellent 1-year graft function, no rejection episodes, good virological control with undetectable HIV RNA, no signs of HIV-associated nephropathy, and no superinfections or opportunistic infections.This case corroborates findings from previous studies showing that kidney transplantation from carefully selected HIV-infected donors to carefully selected HIV-infected recipients seems to be a safe and effective treatment option, and supports the opportunity to expand the organ donor pool for this group of patients with end-stage renal disease.
Topics: Humans; Kidney Transplantation; Tissue Donors; Kidney Failure, Chronic; HIV Infections; RNA; Graft Survival; Graft Rejection
PubMed: 36270737
DOI: 10.1136/bcr-2022-250290 -
PloS One 2022Racial disparities are known in the occurrence of kidney disease with excess risks found among people of African descent. Apolipoprotein L1 (APOL1) gene variants G1 and...
INTRODUCTION
Racial disparities are known in the occurrence of kidney disease with excess risks found among people of African descent. Apolipoprotein L1 (APOL1) gene variants G1 and G2 are associated with kidney disease among HIV infected individuals of African descent in the USA as well as among black population in South Africa. We set out to investigate the prevalence of these high-risk variants and their effects on kidney disease among HIV infected patients in Northern Nigeria with hitherto limited information despite earlier reports of high population frequencies of these alleles from the Southern part of the country.
METHODS
DNA samples obtained from the whole blood of 142 participants were genotyped for APOL1 G1 and G2 variants after initial baseline investigations including assessment of kidney function. Participants comprised 50 HIV positive patients with no evidence of kidney disease, 52 HIV negative individuals with no kidney disease and 40 HIV positive patients with chronic kidney disease (CKD) evidenced by persistent proteinuria and/or reduced eGFR, who also had a kidney biopsy. All the HIV positive patients were newly diagnosed and treatment naïve.
RESULTS
The distribution of the APOL1 genotypes among the study participants revealed that 24.6% had a G1 risk allele and 19.0% a G2. The frequency of the High Risk Genotype (HRG) was 12.5% among those with CKD compared to 5.8% in the HIV negative group and zero in the HIV positive no CKD group. Having the HRG was associated with a higher odds for developing HIV Associated Nephropathy (HIVAN) (2 vs 0 risk alleles: OR 10.83, 95% CI 1.38-84.52; P = 0.023; 2 vs 0 or 1 risk alleles: OR 5.5, 95% CI 0.83-36.29; P = 0.07). The HRG was also associated with higher odds for Focal Segmental Glomerulosclerosis (FSGS) (2 vs 0 risk alleles: OR 13.0, 95% CI 2.06-81.91; P = 0.006 and 2 vs 0 or 1 risk alleles: OR 9.0, 95%CI 1.62-50.12; P = 0.01) when compared to the control group.
CONCLUSION
This study showed a high population frequency of the individual risk alleles of the APOL1 gene with higher frequencies noted among HIV positive patients with kidney disease. There is high association with the presence of kidney disease and especially FSGS and HIVAN among treatment naive HIV patients carrying two copies of the HRG.
Topics: AIDS-Associated Nephropathy; Apolipoprotein L1; Apolipoproteins; Genetic Predisposition to Disease; Genotype; Glomerulosclerosis, Focal Segmental; HIV Infections; Humans; Lipoproteins, HDL; Nigeria; Renal Insufficiency, Chronic; Risk Factors
PubMed: 36227935
DOI: 10.1371/journal.pone.0275949 -
PloS One 2022HIV-associated nephropathy (HIVAN) impairs functions of both glomeruli and tubules. Attention has been previously focused on the HIVAN glomerulopathy. Tubular injury has...
HIV-associated nephropathy (HIVAN) impairs functions of both glomeruli and tubules. Attention has been previously focused on the HIVAN glomerulopathy. Tubular injury has drawn increased attention because sodium wasting is common in hospitalized HIV/AIDS patients. We used viral protein R (Vpr)-transgenic mice to investigate the mechanisms whereby Vpr contributes to urinary sodium wasting. In phosphoenolpyruvate carboxykinase promoter-driven Vpr-transgenic mice, in situ hybridization showed that Vpr mRNA was expressed in all nephron segments, including the distal convoluted tubule. Vpr-transgenic mice, compared with wild-type littermates, markedly increased urinary sodium excretion, despite similar plasma renin activity and aldosterone levels. Kidneys from Vpr-transgenic mice also markedly reduced protein abundance of the Na+-Cl- cotransporter (NCC), while mineralocorticoid receptor (MR) protein expression level was unchanged. In African green monkey kidney cells, Vpr abrogated the aldosterone-mediated stimulation of MR transcriptional activity. Gene expression of Slc12a3 (NCC) in Vpr-transgenic mice was significantly lower compared with wild-type mice, assessed by both qRT-PCR and RNAScope in situ hybridization analysis. Chromatin immunoprecipitation assays identified multiple MR response elements (MRE), located from 5 kb upstream of the transcription start site and extending to the third exon of the SLC12A3 gene. Mutation of MRE and SP1 sites in the SLC12A3 promoter region abrogated the transcriptional responses to aldosterone and Vpr, indicating that functional MRE and SP1 are required for the SLC12A3 gene suppression in response to Vpr. Thus, Vpr attenuates MR transcriptional activity and inhibits Slc12a3 transcription in the distal convoluted tubule and contributes to salt wasting in Vpr-transgenic mice.
Topics: Aldosterone; Animals; Chlorocebus aethiops; Gene Products, vpr; HIV-1; Kidney Tubules, Distal; Mice; Mice, Transgenic; Phosphoenolpyruvate; RNA, Messenger; Receptors, Mineralocorticoid; Renin; Sodium; Sodium Chloride; Sodium Chloride Symporters; Solute Carrier Family 12, Member 3; Thiazides
PubMed: 36129874
DOI: 10.1371/journal.pone.0273313 -
Kidney International Oct 2022Four decades after the first cases of HIV were reported, kidney disease remains an important comorbidity in people with HIV (PWH). Both HIV-associated nephropathy and... (Review)
Review
Four decades after the first cases of HIV were reported, kidney disease remains an important comorbidity in people with HIV (PWH). Both HIV-associated nephropathy and immune complex kidney disease were recognized as complications of HIV infection in the early years before treatment was available. Although the introduction of effective antiretroviral therapy in the late 1990s resulted in dramatic improvements in survival and health in PWH, several commonly used antiretroviral agents have been associated with kidney injury. HIV infection and treatment may also promote the progression of comorbid chronic kidney disease due to traditional risk factors such as diabetes, and HIV is one of the strongest "second hits" for the high-risk APOL1 genotype. Unique considerations in the management of chronic kidney disease in PWH are largely related to the need for lifelong antiretroviral therapy, with potential for toxicity, drug-drug interactions, and polypharmacy. PWH who develop progressive chronic kidney disease are candidates for all modalities of kidney replacement therapy, including kidney transplantation, and at some centers, PWH may be candidates to serve as donors for recipients with HIV. Transplantation of kidney allografts from donors with HIV also offers a unique opportunity to study viral dynamics in the kidney, with implications for kidney health and for research toward HIV cure. In addition, HIV-transgenic animal models have provided important insights into kidney disease pathogenesis beyond HIV, and experience with HIV and HIV-related kidney disease has provided important lessons for future pandemics.
Topics: AIDS-Associated Nephropathy; Animals; Anti-Retroviral Agents; Antigen-Antibody Complex; Apolipoprotein L1; HIV Infections; Humans; Renal Insufficiency, Chronic
PubMed: 35850290
DOI: 10.1016/j.kint.2022.06.021 -
PloS One 2022The spectrum of HIV-associated kidney disease has expanded significantly with the introduction of antiretroviral therapy (ART). In the pre-ART era there was prominence...
The spectrum of HIV-associated kidney disease has expanded significantly with the introduction of antiretroviral therapy (ART). In the pre-ART era there was prominence of HIV-associated nephropathy (HIVAN). More recently, the spectrum of disease additionally reflects comorbid illness in the ageing HIV population and ART-related nephrotoxicity. We performed a clinicopathological correlation of kidney disease in HIV-positive individuals who underwent kidney biopsy between 1989 and 2014, utilizing the 2018 Kidney Disease Improving Global Outcomes pathologic classification. ART rollout began in 2004 in South Africa. Patients biopsied pre-ART rollout were compared to those biopsied post-ART rollout with respect to demographics, clinical parameters and histology. We assessed kidney survival in a cohort of these patients following biopsy. Six hundred and ninety biopsies were included, 99 (14.3%) were undertaken pre- and 591 (85.7%) post-ART rollout. Most patients were of Black African descent (97.5%). The post-ART rollout patients were older (p = 0.007), had higher eGFR at presentation (p = 0.016) and fewer presented with eGFR of less than 15ml/min/1.73m2 (p = 0.0008). There was a decrease in the prevalence of classic HIVAN (p = 0.00001); and an increase in FSGS (NOS) in the setting of HIV (p = 0.0022) and tubulointerstitial diseases (p = 0.009) post-ART rollout. Kidney function survival over 5 years was poorest in patients with classic HIVAN (p = 0.00005) and best in minimal change nephropathy (p = 0.0013). Kidney biopsy is crucial for the correct diagnosis and management of HIV-related kidney disease. ART rollout has shifted the spectrum of kidney disease away from classic HIVAN but has not eliminated it. Histological diagnosis prognosticates kidney survival.
Topics: AIDS-Associated Nephropathy; Cohort Studies; HIV Infections; Humans; Kidney; Prevalence
PubMed: 35639767
DOI: 10.1371/journal.pone.0269260 -
Viruses Apr 2022The achievement of an HIV cure is dependent on the eradication or permanent silencing of HIV-latent viral reservoirs, including the understudied central nervous system...
The achievement of an HIV cure is dependent on the eradication or permanent silencing of HIV-latent viral reservoirs, including the understudied central nervous system (CNS) reservoir. This requires a deep understanding of the molecular mechanisms of HIV's entry into the CNS, latency establishment, persistence, and reversal. Therefore, representative CNS culture models that reflect the intercellular dynamics and pathophysiology of the human brain are urgently needed in order to study the CNS viral reservoir and HIV-induced neuropathogenesis. In this study, we characterized a human cerebral organoid model in which microglia grow intrinsically as a CNS culture model to study HIV infection in the CNS. We demonstrated that both cerebral organoids and isolated organoid-derived microglia (oMG), infected with replication-competent HIVbal reporter viruses, support productive HIV infection via the CCR5 co-receptor. Productive HIV infection was only observed in microglial cells. Fluorescence analysis revealed microglia as the only HIV target cell. Susceptibility to HIV infection was dependent on the co-expression of microglia-specific markers and the CD4 and CCR5 HIV receptors. Altogether, this model will be a valuable tool within the HIV research community to study HIV-CNS interactions, the underlying mechanisms of HIV-associated neurological disorders (HAND), and the efficacy of new therapeutic and curative strategies on the CNS viral reservoir.
Topics: AIDS-Associated Nephropathy; HIV Infections; HIV-1; Humans; Microglia; Organoids; Receptors, HIV
PubMed: 35458559
DOI: 10.3390/v14040829 -
Journal of the International... 2022Kidney disease is the fourth most common cause of non-AIDS-related mortality in people living with HIV. Combination antiretroviral therapy (cART) remains the cornerstone...
Kidney disease is the fourth most common cause of non-AIDS-related mortality in people living with HIV. Combination antiretroviral therapy (cART) remains the cornerstone of treatment. However, little is known about the impact of cART on disease outcomes in patients with HIV-associated nephropathy (HIVAN) and HIV-immune complex kidney disease (HIVICK). This systematic review evaluates the impact of cART on progression to end-stage kidney disease (ESKD) and other outcomes in HIV-infected individuals. We conducted a literature search utilizing PubMed, and Cochrane database and 11 articles met inclusion criteria for analysis of which nine HIVAN studies showed decreased progression to ESKD or death for subjects when treated with cART versus those untreated. However, two studies showed no survival advantage with cART. Three HIVICK studies showed improvement in delaying ESKD in subjects on cART compared to untreated subjects. cART appeared to reduce the risk to ESKD or death in patients with both HIVAN and HIVICK.
Topics: AIDS-Associated Nephropathy; HIV Infections; Humans
PubMed: 35369795
DOI: 10.1177/23259582221089194