Apolipoprotein L1 gene variants and kidney disease in patients with HIV: a systematic review and meta-analysis.

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.

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.

High risk APOL1 genotypes and kidney disease among treatment naïve HIV patients at Kano, Nigeria.

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.

Kidney Transplantation in HIV-positive Patients: Current Practice and Management Strategies.

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.

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.

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.

Prevalence and Pattern of Human Immunodeficiency Virus-Associated Nephropathy among Human Immunodeficiency Virus-Positive Children at the University of Maiduguri Teaching Hospital, Nigeria.

The kidney is an important target organ in human immunodeficiency virus (HIV) infection, and a variety of renal disorders could occur throughout the course of the disease. HIV- associated nephropathy (HIVAN) is the most common form of kidney disease resulting directly from HIV infection. The true prevalence of HIVAN among infected African children is unknown largely due to lack of surveillance and reporting. We thus aimed to determine the prevalence of HIVAN and associated factors among HIV-infected children at the University of Maiduguri Teaching Hospital. This was a cross-sectional study carried out at the Pediatric Infectious Clinic. Children aged ≤15 years were recruited through systematic random sampling. Relevant sociodemographic and clinical information were obtained. Spot urine sample was analyzed using a multistix (Combi-Screen 10SL Analyticon Biotechnologies AG, Germany), and proteinuria of ≥2+ was considered significant. The CD4+ count and CD4+% (for those <5 years) were obtained using a PARTEC™ CD4+ easy count kit. The obtained data were entered and analyzed using Statistical Package for the Social Sciences version 16.0. A total of 250 children were recruited. Eighty-five (34%) of them had HIVAN. Sex, social class, and mode of transmission were not significantly associated with HIVAN (P >0.05). However, age, medication status (highly active antiretroviral therapy [HAART]), duration on HAART, and disease severity (both clinical and immunological) all had a significant association to HIVAN (p = 0.005, 0.004, 0.008, and <0.001, respectively). These factors also showed a positive but weak correlation to HIVAN; while age had the least correlation coefficient (0.157), immunological class had the highest r = 0.458. However, these relationships were all significant (P <0.5). HIVAN is highly prevalent among children living with HIV in Maiduguri. Routine screening through urina-lysis and early commencement of HAART is recommended.

Fibrillary glomerulonephritis in a human immunodeficiency virus-positive, hepatitis C-negative Indian patient: Expanding the profile of renal involvement in human immunodeficiency virus infection.

Highly active anti retroviral therapy (HAART) has dramatically improved life expectancy of human immunodeficiency virus (HIV) infected patients, converting HIV infection into a chronic illness with associated changes in its attendant renal complications. The past two decades have witnessed a decrease in the prevalence of HIV associated nephropathy (HIVAN), traditionally considered to be the hall mark of renal involvement in HIV infection. Simultaneously a host of other glomerular and tubulo-interstitial diseases have emerged, expanding the spectrum of HIV associated renal diseases, predominant among which is HIV associated immune complex mediated kidney diseases (HIVICK). Of the diverse glomerular diseases constituting HIVICK, fibrillary glomerulonephritis (FGN) remains a rarity, with only two existing reports to date, confined to patients co-infected with Hepatitis C virus (HCV). The pathogenetic role of HIV in these patients remains under a cloud because of previously well established association of HCV infection and FGN. We report a case of FGN in a HIV seropositive, HCV negative Indian patient, highlighting the diagnostic electron microscopy (EM) findings of FGN and strengthening the causal association of HIV with FGN. In view of increasing heterogeneity of renal complications in HIV infection, the diagnostic utility of a comprehensive renal biopsy evaluation inclusive of EM is emphasized for appropriate selection of treatment modalities.

Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

HIV-positive individuals are at increased risk for kidney disease, including HIV-associated nephropathy, noncollapsing focal segmental glomerulosclerosis, immune-complex kidney disease, and comorbid kidney disease, as well as kidney injury resulting from prolonged exposure to antiretroviral therapy or from opportunistic infections. Clinical guidelines for kidney disease prevention and treatment in HIV-positive individuals are largely extrapolated from studies in the general population, and do not fully incorporate existing knowledge of the unique HIV-related pathways and genetic factors that contribute to the risk of kidney disease in this population. We convened an international panel of experts in nephrology, renal pathology, and infectious diseases to define the pathology of kidney disease in the setting of HIV infection; describe the role of genetics in the natural history, diagnosis, and treatment of kidney disease in HIV-positive individuals; characterize the renal risk-benefit of antiretroviral therapy for HIV treatment and prevention; and define best practices for the prevention and management of kidney disease in HIV-positive individuals.

Chronic kidney disease in Australian Human Immunodeficiency Virus-infected patients: Analysis of the Australian HIV Observational Database.

AIM: The aim of the present study was to examine data from the Australian HIV Observational Database (AHOD), and firstly, to describe the incidence of chronic kidney disease (CKD) and the rate of loss of renal function in HIV-infected individuals living in Australia, and then to examine the risk factors contributing to CKD in this population. METHODS: AHOD patients over 18 years of age were eligible if they had at least two serum creatinine measurements from 1 April 2008 until 31 March 2016 and an initial estimated glomerular filtration rate (eGFR) greater than 60 mL/min per 1.73 m3 . Cox proportional hazards models were used to assess risk factors for CKD, which included key patient demographic data and antiretroviral therapy (ART) exposure. RESULTS: Of 1924 patients included in the analysis between April 2008 and March 2016, 81 (4.2%) developed CKD (confirmed eGFR of less than 60 mL/min per 1.73 m3 through two consecutive eGFR measurements at least 3 months apart). Of the examined risk factors, baseline age, baseline eGFR, and the route of HIV acquisition were statistically significant predictors of development of CKD. ART exposure, viral hepatitis co-infection, high viral load and low CD4 lymphocyte count were not found to be significant risk factors for CKD. CONCLUSION: This is the first study to investigate the risk factors for development of CKD among Australian HIV-infected patients using cohort data. It highlights the need for awareness of renal risk factors, particularly among older patients or in those with pre-existing renal dysfunction. Further research is required to explore the discrepancy between patients who have acquired HIV through different means of exposure.

Renal transplantation in HIV-positive patients - No more a scare!

Human immunodeficiency virus (HIV) infection has posed as a major global health epidemic for almost three decades. With the advent of highly active antiretroviral therapy in 1996 and the application of prophylaxis and management of opportunistic infections, acquired immunodeficiency syndrome mortality has decreased markedly. The most aggressive HIV-related renal disease is end-stage renal disease due to HIV-associated nephropathy. Presence of HIV infection used to be viewed as a contraindication to renal transplantation for multiple reasons; concerns for exacerbation of an already immunocompromised state by administration of additional immunosuppressants; the use of a limited supply of donor organs with unknown long-term outcomes. Multiple studies have reported promising outcomes at three to five years after kidney transplantations in patients treated with highly active antiretroviral therapy, and HIV is no longer a contraindication for renal transplant. Hence, we present eight HIV-positive patients who received live-related renal transplantation at our center and their follow-up.

Short Communication: The Clinical Value of Cystatin C as a Marker of Renal Function in HIV Patients Receiving Dolutegravir.

Dolutegravir (DTG) is an integrase strand transfer inhibitor that is used for the treatment of HIV infection. DTG inhibits organic cation transporter 2 on the basolateral side of proximal tubule cells of the kidney and leads to increased serum creatinine levels without true renal function deterioration. In HIV patients who receive DTG, an alternative test to serum creatinine measurement is needed to determine the correct renal function. We retrospectively evaluated 18 HIV-infected men who had received combination antiretroviral therapy (cART), including DTG, and who had available data on serum creatinine and cystatin C levels. We used paired t-test to assess the changes in estimated glomerular filtration rate (eGFR) calculated by serum creatinine or cystatin C level, after the start of cART. In all 18 patients, only 2 cases were naive, whereas 16 cases switched treatment. Based on serum creatinine level, eGFR significantly changed from 67.9 (61.2-95.7) ml/min per 1.73 m2 [medians and interquartile ranges ] to 63.6 (55.5-83.7) ml/min per 1.73 m2 (p = .0004). Conversely, eGFR was almost unchanged [79.8 (77.7-82.5) to 80.0 (77.1-82.5) ml/min per 1.73 m2; p = .132] when serum cystatin C level was used for estimation. In HIV patients receiving DTG, measurement of serum cystatin C as an alternative renal function test might be clinically valuable because it is not affected by DTG administration.

HIV Infection in the Native and Allograft Kidney: Implications for Management, Diagnosis, and Transplantation.

The native kidney is a reservoir for human immunodeficiency virus (HIV)-1 and a site of viral replication, similar to lymphoid tissue, gut-associated lymphoid tissue or semen. The ability of the virus to persist may result from either a true latency or sequestration in an anatomic site that is not effectively exposed to antiretroviral therapy. The presence of HIV in kidney epithelial cells will lead progressively to end-stage renal disease. For decades, HIV-infected patients were excluded from consideration for kidney transplantation. Hemodialysis and peritoneal dialysis were the only forms of treatment available to these patients. The introduction of combined antiretroviral therapy has changed the overall prognosis of these patients and allowed them to benefit from kidney transplantation without an increased risk of opportunistic infections or cancer. However, we recently established that HIV-1 can infect kidney transplant epithelial cells in the absence of detectable viremia. The presence of HIV in kidney cells can manifest itself in multiple ways, ranging from indolent nephropathy and inflammation to proteinuria with glomerular abnormalities. Because the tools that are available to diagnose the presence of HIV in kidney cells are complex, the rate of infection is certainly underestimated. This finding will certainly have implications in the management of patients, particularly for HIV-positive donors. The purpose of this review is to highlight recent evidence that the allograft kidney can be infected by the virus after transplantation as well as the associated consequences.

Screening and management practices for renal disease in the HIV-positive patient population of an inner metropolitan sexual health service.

Renal disease is an important and commonly encountered co-morbidity in HIV infection. Despite this, few data are available concerning renal disease in this patient group. A retrospective review was conducted of all HIV-positive patients of an inner metropolitan sexual health service who attended from 1 August 2013 to 31 July 2014 for HIV management. One hundred eighty-eight HIV-positive patients attended the clinic during the study period. The majority were male (96%), Caucasian (70%) and 30-39 years of age (37%). There was a high prevalence of renal risk factors in the population, including potentially nephrotoxic antiretroviral therapy (61%), smoking (38%), hypertension (12%), dyslipidemia (11%) and hepatitis C co-infection (7%). In the previous year, measurements of estimated glomerular filtration rate were performed in all patients, but measurements of lipid profiles, urinary protein and serum phosphate were performed within the last year in only 48%, 33% and 30% of patients, respectively. These are the first comprehensive data regarding renal disease, associated risk factors and screening and management practices in the HIV-positive patient population of a specialized sexual health service in Australia. This patient population demonstrates a particularly high prevalence of risk factors for renal disease. Despite this, screening investigations were not performed as recommended. This represents a potential area to improve patient care.

Refinement of the HIVAN1 Susceptibility Locus on Chr. 3A1-A3 via Generation of Sub-Congenic Strains.

HIV-1 transgenic mice on the FVB/NJ background (TgFVB) represent a validated model of HIV-associated nephropathy (HIVAN). A major susceptibility locus, HIVAN1, was previously mapped to chromosome 3A1-A3 in a cross between TgFVB and CAST/EiJ (CAST) strains, and introgression of a 51.9 Mb segment encompassing HIVAN1 from CAST into TgFVB resulted in accelerated development of nephropathy. We generated three sub-congenic strains carrying CAST alleles in the proximal or distal regions of the HIVAN1 locus (Sub-II, 3.02-38.93 Mb; Sub-III, 38.45-55.1 Mb and Sub-IV, 47.7-55.1 Mb, build 38). At 5-10 weeks of age, histologic injury and proteinuria did not differ between HIV-1 transgenic Sub-II and TgFVB mice. In contrast, HIV-1 transgenic Sub-III and Sub-IV mice displayed up to 4.4 fold more histopathologic injury and 6-fold more albuminuria compared to TgFVB mice, similar in severity to the full-length congenic mice. The Sub-IV segment defines a maximal 7.4 Mb interval for HIVAN1, and encodes 31 protein coding genes: 15 genes have missense variants differentiating CAST from FVB, and 14 genes show differential renal expression. Of these, Frem1, Foxo1, and Setd7 have been implicated in the pathogenesis of nephropathy. HIVAN1 congenic kidneys are histologically normal without the HIV-1 transgene, yet their global transcriptome is enriched for molecular signatures of apoptosis, adenoviral infection, as well as genes repressed by histone H3 lysine 27 trimethylation, a histone modification associated with HIV-1 life cycle. These data refine HIVAN1to 7.4 Mb and identify latent molecular derangements that may predispose to nephropathy upon exposure to HIV-1.