Targeting WIP1 phosphatase promotes partial remission in experimental collapsing glomerulopathy.

Collapsing focal segmental glomerulosclerosis (FSGS), also known as collapsing glomerulopathy (CG), is the most aggressive variant of FSGS and is characterized by a rapid progression to kidney failure. Understanding CG pathogenesis represents a key step for the development of targeted therapies. Previous work implicated the telomerase protein component TERT in CG pathogenesis, as transgenic TERT expression in adult mice resulted in a CG resembling that seen in human primary CG and HIV-associated nephropathy (HIVAN). Here, we used the telomerase-induced mouse model of CG (i-TERTci mice) to identify mechanisms to inhibit CG pathogenesis. Inactivation of WIP1 phosphatase, a p53 target acting in a negative feedback loop, blocked disease initiation in i-TERTci mice. Repression of disease initiation upon WIP1 deficiency was associated with senescence enhancement and required transforming growth factor-ß functions. The efficacy of a pharmacologic treatment to reduce disease severity in both i-TERTci mice and in a mouse model of HIVAN (Tg26 mice) was then assessed. Pharmacologic inhibition of WIP1 enzymatic activity in either the telomerase mice with CG or in the Tg26 mice promoted partial remission of proteinuria and ameliorated kidney histopathologic features. Histological as well as high-throughput sequencing methods further showed that selective inhibition of WIP1 does not promote kidney fibrosis or inflammation. Thus, our findings suggest that targeting WIP1 may be an effective therapeutic strategy for patients with CG.

NEF-Induced HIV-Associated Nephropathy Through HCK/LYN Tyrosine Kinases.

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.

Undiagnosed HIV in Patients on Immunosuppressive Medications Presenting with HIV-Associated Kidney Disease.

Approximately 158,500 adults and adolescents in the United States live with undiagnosed human immunodeficiency virus (HIV). Missed or delayed diagnoses adversely affect disease management and outcomes. This is particularly salient for patients receiving immunosuppressive and immunomodulatory therapy for the management of chronic inflammatory conditions, in which additional immunosuppression may increase the risk and severity of opportunistic infections. Despite this risk, comprehensive HIV testing before the initiation of immunosuppressive therapy is not yet the norm. We describe a case series containing the narratives of three patients recently treated with immunosuppressive agents, who presented with signs concerning for HIV-associated kidney diseases and who were found to have undiagnosed HIV later in the treatment course, which, unfortunately, resulted in poor outcomes. Screening for HIV or related illnesses, such as viral hepatitis or mycobacterial co-infections including tuberculosis, is essential before initiating biologic immunosuppression.

Tubular-specific expression of HIV protein Vpr leads to severe tubulointerstitial damage accompanied by progressive fibrosis and cystic development.

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.

HIV-1 infection of renal epithelial cells: 30 years of evidence from transgenic animal models, human studies and in vitro experiments.

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.

Updates on HIV and Kidney Disease.

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.

HIV-associated nephropathy in children: challenges in a resource-limited setting.

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.

GWAS in Mice Maps Susceptibility to HIV-Associated Nephropathy to the Ssbp2 Locus.

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 Ssbp2 as the most likely candidate gene. Ssbp2 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 Ssbp2 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 Ssbp2 as susceptibility gene for HIVAN, potentially acting via the LDB1-LMX1B transcriptional network.

HIV at 40: kidney disease in HIV treatment, prevention, and cure.

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.

The spectrum of kidney biopsy findings in Chinese HIV-infected patients.

OBJECTIVES: HIV-associated kidney disease is common but data on the pathology spectrum of kidney biopsy in China is lacking. This study aimed to illustrate the clinical presentation, laboratory findings and pathological spectrum of different subtypes of HIV-associated kidney disease in China. METHODS: Eighteen HIV patients with renal biopsy indications at the Peking Union Medical College Hospital from January 2002 to October 2021 were retrospectively enrolled. All had CD4 counts and HIV viral load measurements. Renal biopsies were examined with light microscopy, immunofluorescence, and electron microscopy. Shapiro-Wilk test was used to test whether the data was normally distributed. The data is presented as medians (interquartile range), number (%), or means (±SD) according to their distribution. RESULTS: Seventeen patients had glomerular disease, and one patient had interstitial nephritis. Membranous nephropathy was present in eight patients (47.1%), and IgA nephropathy in four patients (23.5%). The difference in urine protein and serum albumin before and after treatment was statistically significant and no deaths or dialysis were observed to the end of follow-up. CONCLUSION: This study found that classic HIV-associated nephropathy (HIVAN) was uncommon in Chinese HIV patients. HIV immune complex kidney (HIVICK) disease, such as membranous or IgA nephropathy, was more common, and associated with better prognosis. Antiretroviral therapy, ACE inhibitors, and angiotensin II receptor blockers were effective in decreasing proteinuria and preserving renal function. The use of corticosteroids and immunosuppressive agents seems safe. However, the nephrotoxic effect of antiretroviral agents and other medications should be carefully monitored.

Effects of HIV Infection on Arterial Endothelial Function: Results From a Large Pooled Cohort Analysis.

OBJECTIVE: To determine the effects of HIV serostatus and disease severity on endothelial function in a large pooled cohort study of people living with HIV infection and HIV- controls. Approach and Results: We used participant-level data from 9 studies: 7 included people living with HIV (2 treatment-naïve) and 4 had HIV- controls. Brachial artery flow-mediated dilation (FMD) was measured using a standardized ultrasound imaging protocol with central reading. After data harmonization, multiple linear regression was used to examine the effects of HIV- serostatus, HIV disease severity measures, and cardiovascular disease risk factors on FMD. Of 2533 participants, 986 were people living with HIV (mean 44.4 [SD 11.8] years old) and 1547 were HIV- controls (42.9 [12.2] years old). The strongest and most consistent associates of FMD were brachial artery diameter, age, sex, and body mass index. The effect of HIV+ serostatus on FMD was strongly influenced by kidney function. In the highest tertile of creatinine (1.0 mg/dL), the effect of HIV+ serostatus was strong (ß=-1.59% [95% CI, -2.58% to -0.60%], P=0.002), even after covariate adjustment (ß=-1.36% [95% CI, -2.46% to -0.47%], P=0.003). In the lowest tertile (0.8 mg/dL), the effect of HIV+ serostatus was strong (ß=-1.90% [95% CI, -2.58% to -1.21%], P<0.001), but disappeared after covariate adjustment. HIV RNA viremia, CD4+ T-cell count, and use of antiretroviral therapy were not meaningfully associated with FMD. CONCLUSIONS: The significant effect of HIV+ serostatus on FMD suggests that people living with HIV are at increased cardiovascular disease risk, especially if they have kidney disease.

Inhibition of apoptosis signal-regulating kinase 1 mitigates the pathogenesis of human immunodeficiency virus-associated nephropathy.

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.

Childhood HIV-associated nephropathy: 36 years later.

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.

Prevalence and risk factors of chronic kidney disease in an HIV positive Mexican cohort.

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.

HIV-Associated Nephropathy among Children with Renal Disease in Port Harcourt, Nigeria.

INTRODUCTION: Human Immunodeficiency Virus (HIV) infects multiple tissues of the body, including the renal parenchyma, with HIV-associated Nephropathy (HIVAN) being the most common form of the HIV-related renal disease and an important cause of End Stage Renal Disease (ESRD) in HIV infected patients. There is paucity of studies on HIVAN among children with renal diseases, most studies on HIVAN focused on prevalence among HIV patients with vertical transmission being the commonest route. We undertook this study to determine the prevalence and impact of HIVAN among our renal patients and to highlight the new route of HIV transmission observed in these group of patients in Port Harcourt, Southern Nigeria. MATERIALS AND METHODS: The study was conducted among renal patients managed in the Paediatric department of the University of Port Harcourt Teaching Hospital from December 2016 to March 2019. The information on the HIVAN patients were stored and retrieved from the renal register where all cases of renal diseases were enrolled. The diagnosis of HIVAN was made based on presence of significant proteinuria (≥ 1+), with one or more of the following: abnormal microscopic examination of urinary sediments, rising serum creatinine, renal ultrasound finding of enlarged echogenic kidneys and histology finding of focal segmental glomerulosclerosis. The patient's sociodemographic data, clinical presentation, route of transmission of HIV, laboratory investigations, treatment, and clinical outcome were obtained and analysed using SPSS version 25.0. RESULTS: There were 112 cases of renal diseases seen during the study period of which 10 (8.9%) had HIVAN. The HIVAN patients were aged between 4-17years. Four (40%) of these HIVAN cases had CKD of which 2 (20%) had ESRD. The route of transmission of HIV was vertical (mother-to-child) in 8 patients and via sexual route in two older male patients aged 17years who were homosexuals. Mortality rate among the HIVAN patients was 30%, with 2 (20%) lost to follow up. CONCLUSION: There is a rising prevalence of HIVAN among paediatric patients with renal diseases in our environment, with homosexuality being a new route of HIV transmission observed in the older patients.

INTRODUCTION: Le virus de l'immunodéficience humaine (VIH) infecte plusieurs tissus du corps, y compris le parenchyme rénal, la néphropathie associée au VIH (VIHAN) étant la forme la plus courante d'insuffisance rénale liée au VIH et une cause importante de maladie rénale en phase terminale (IRT) chez les patients infectés par le VIH. Il y a peu d'études sur le VIHAN chez les enfants atteints de maladies rénales, la plupart des études sur le VIHAN se concentrant sur la prévalence chez les patients VIH avec transmission verticale étant la voie la plus courante. Nous avons entrepris cette étude pour déterminer la prévalence et l'impact du VIHAN chez nos patients rénaux et pour mettre en évidence la nouvelle voie de transmission du VIH observée dans ce groupe de patients à Port Harcourt, dans le sud du Nigeria. MATÉRIAUX ET MÉTHODES: L'étude a été menée auprès de patients rénaux pris en charge dans le service de pédiatrie de l'hôpital universitaire de l'Université de Port Harcourt de décembre 2016 à mars 2019. Les informations sur les patients VIHAN ont été stockées et extraites du registre rénal où tous les cas de maladies rénales ont été inscrits. Le diagnostic de VIHAN a été posé sur la base de la présence d'une protéinurie significative (≥ 1+), avec un ou plusieurs des éléments suivants: examen microscopique anormal des sédiments urinaires, augmentation de la créatinine sérique, détection par échographie rénale de reins échogènes hypertrophiés et observation histologique du segment focal glomérulosclérose. Les données sociodémographiques, la présentation clinique, la voie de transmission du VIH, les examens de laboratoire, le traitement et les résultats cliniques du patient ont été obtenus et analysés à l'aide de la version 25.0 de SPSS. RÉSULTATS: Il y a eu 112 cas de maladies rénales observés au cours de la période d'étude, dont 10 (8,9%) avaient HIVAN. Les patients HIVAN étaient âgés de 4 à 17 ans. Quatre (40%) de ces cas de VIHAN avaient une IRC dont 2 (20%) avaient une IRT. La voie de transmission du VIH était verticale (mère-enfant) chez 8 patients et par voie homosexuelle chez deux patients masculins âgés de 17 ans. Le taux de mortalité parmi les patients VIHAN était de 30%, avec 2 (20%) perdus de vue. CONCLUSION: Il y a une prévalence croissante du VIHAN chez les patients pédiatriques atteints de maladies rénales dans notre environnement, l'homosexualité étant une nouvelle voie de transmission du VIH observée chez les patients plus âgés. MOTS CLÉS: Néphropathie associée au VIH, prévalence, résultat, homosexualité.

PATHOMORPHOLOGICAL CHARACTERISTICS OF IMMUNOCOMPLEX RENAL DISEASE IN PATIENTS WITH IMMUNODEFICIENCY VIRUS AND HEPATITIS C VIRUS, RECEIVING ANTIRETROVIRAL THERAPY.

OBJECTIVE: The aim is to verify and describe the morphological substrate of renal impairment in HIV/HCV co-infection among patients receiving ART to assess and predict the morphogenesis of immunocomplex lesions. PATIENTS AND METHODS: Materials and methods: To assess and predict the morphogenesis of immunocomplex renal disease, we examined retrospectively the kidney tissue samples of 15 patients, who died with HIV/HCV co-infection and received ART. Histological, histochemical and immunohistochemical research methods were used. RESULTS: Results: Segmental and diffuse mesangial proliferation with extracellular matrix expansion with glomerular damage ≥50% in 9 (60%) cases, and involving <50% of glomeruli in 5 (33%), with CD68 expression as single cells were detected. In 12 (80%) cases, there was uneven swelling and focal proliferation of endothelial cells with the involvement of 20-50% of the glomeruli, as well as the presence of cellular infiltrates in the lumen of capillary loops in 3 (20%) cases with monomorphic intensity in "+". Sclerotic changes were present in various degrees of severity - from cases of complete glomerulosclerosis with obliteration of the Bowman's lumen to focal and microfocal depressions 8 (55%), sclerosis 10 (66%), hyalinosis 1 (6%), uneven thickening, focal cleft 8 (55%) and perihilar focal sclerosis. These areas were positive for IgG and C1q complement fractions within the "+", "++" intensity. Among the study group, no case of HIV-associated nephropathy was found that coincided with the predicted spectrum of kidney damage for patients in this sample. The described morphological changes were mainly verified as immuno-mediated by HCV. CONCLUSION: Conclusions: A comprehensive morphological study revealed the morphological substrate of kidney damage and its morphogenesis in patients with HIV/HCV co-infection, receiving ART.

Role of SIRT1 in HIV-associated kidney disease.

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.

The spectrum of kidney biopsy findings in HIV-infected patients in the modern era.

HIV-associated kidney disease is evolving rapidly. Few North American studies have addressed modern trends and none has applied the 2018 Kidney Disease Improving Global Outcomes (KDIGO) pathologic classification. Therefore we performed a retrospective clinical-pathologic analysis of all HIV-positive patients with kidney biopsy interpreted at Columbia University from 2010-2018 using the KDIGO classification. The biopsy cohort of 437 HIV-positive patients had median age 53 years, including 66% males, 80% on anti-retroviral therapy, 57% with hypertension, 31% with diabetes, 27% with hepatitis C and 6% with hepatitis B co-infections. Race, known in 308 patients, included 58% black, 25% white and 17% Hispanic. Pathologic diagnoses were surprisingly diverse. Immune complex glomerulonephritis (ICGN) and diabetic nephropathy each outnumbered HIV-associated nephropathy, followed by tenofovir nephrotoxicity, FSGS- not otherwise specified (NOS) and global sclerosis (NOS). HIV-associated nephropathy was the most common disease in patients not on anti-retroviral therapy, and 94% were black. The association of FSGS (NOS) with black race (68%) and anti-retroviral therapy use (77%) suggests some cases may represent attenuated HIV-associated nephropathy. The most common ICGNs were IgA nephropathy and membranous glomerulopathy, both associating with anti-retroviral therapy (over 90%), followed by hepatitis C-associated proliferative ICGN. Among the 16 cases of uncharacterized ICGN lacking identifiable etiology, 69% were not on anti-retroviral therapy, possibly representing true HIV-associated immune complex kidney disease. Dual diseases occurred in 17% of patients, underscoring lesion complexity. Thus, anti-retroviral therapy has shifted the landscape of HIV-associated kidney disease toward diverse ICGN, diabetic nephropathy, and non-collapsing glomerulosclerosis, but has not eradicated HIV-associated nephropathy.

Patients with human immunodeficiency virus infection do not have inferior outcomes after dialysis access creation.

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.

Inflammasome activation in podocytes: a new mechanism of glomerular diseases.

INTRODUCTION: Inflammasome is a multi-protein complex which is an important constituent of innate immunity. It mainly consists of three parts, apoptosis-associated speck-like protein containing caspase recruitment domain (ASC), caspase protease, and a NOD-like receptor (NLR) family protein (such as NLRP1) or an HIN200 family protein (such as AIM2). Inflammasome is widely studied in many autoimmune diseases and chronic inflammatory reactions, such as familial periodic autoinflammatory response, type 2 diabetes, Alzheimer's disease, and atherosclerosis. Activation of inflammasome in the kidney has been widely reported in glomerular and tubular-interstitial diseases. Podocytes play a critical role in maintaining the normal structure and function of glomerular filtration barrier. Recently, it has been demonstrated that podocytes, as a group of renal residential cells, can express all necessary components of NLRP3 inflammasome, which is activated and contribute to inflammatory response in the local kidney. METHODS: Literature review was conducted to further summarize current evidence of podocyte NLRP3 inflammasome activation and related molecular mechanisms under different disease conditions. RESULTS: Podocytes are a key component of the glomerular filtration barrier, and the loss of podocyte regeneration is a major limiting factor in the recovery of proteinuria. Through a more comprehensive study of inflammasome in podocytes, it will provide new targets and possibilities for the treatment of kidney diseases.