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.

Regional and Racial Disparities in HIV-Related Kidney Disease.

Clinical Background and Epidemiology: Worldwide, an estimated 38 million people are living with HIV infection. The classic kidney disease of HIV infection, commonly known as HIV-associated nephropathy, is a collapsing form of focal segmental glomerulosclerosis that almost exclusively affects individuals of African descent with advanced HIV disease. People living with HIV are also at risk for immune-complex kidney diseases, antiretroviral nephrotoxicity, and kidney disease due to co-infections and comorbidities. Challenges: The burden of HIV-related kidney disease is greatest in traditionally disadvantaged populations in resource-limited settings in sub-Saharan Africa and the Caribbean and among minority populations in the United States and Europe. Factors contributing to these disparities include a higher prevalence of HIV infection, limited access to optimal antiretroviral therapy, and genetic susceptibility to kidney disease. Treatment and Prevention: Current treatment guidelines recommend the initiation of life-long antiretroviral therapy in all people living with HIV to prevent AIDS and non-AIDS complications, including kidney disease. People living with HIV who progress to end-stage kidney disease despite treatment are candidates for dialysis and kidney transplant, including the possibility of accepting organs from HIV-positive donors in some settings. Although HIV prevention is currently the only definitive solution, expanding access to antiretroviral therapy, dialysis, and kidney transplantation in people living with HIV are important intermediate steps to address the global burden of HIV-related kidney disease.

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.

Viral Vector-Mediated Gene Transfer of Glutamic Acid Decarboxylase for Chronic Pain Treatment: A Literature Review.

Chronic pain is long-lasting nociceptive state, impairing the patient's quality of life. Existing analgesics are generally not effective in the treatment of chronic pain, some of which such as opioids have the risk of tolerance/dependence and overdose death with higher daily opioid doses for increasing analgesic effect. Opioid use disorders have already reached an epidemic level in the United States; therefore, nonopioid analgesic approach and/or use of nonpharmacologic interventions will be employed with increasing frequency. Viral vector-mediated gene therapy is promising in clinical trials in the nervous system diseases. Glutamic acid decarboxylase (GAD) enzyme, a key enzyme in biosynthesis of γ-aminobutyric acid (GABA), plays an important role in analgesic mechanism. In the literature review, we used PubMed and bioRxiv to search the studies, and the eligible criteria include (1) article written in English, (2) use of viral vectors expressing GAD67 or GAD65, and (3) preclinical pain models. We identified 13 eligible original research articles, in which the pain models include nerve injury, HIV-related pain, painful diabetic neuropathy, and formalin test. GAD expressed by the viral vectors from all the reports produced antinociceptive effects. Restoring GABA systems is a promising therapeutic strategy for chronic pain, which provides evidence for the clinical trial of gene therapy for pain in the near future.

HIV/AIDS and chronic kidney disease.

Chronic kidney disease (CKD) is a frequent complication of HIV infection. The classic involvement of the kidney by HIV infection is HIV-associated nephropathy (HIVAN), occurring typically in young adults of African ancestry with advanced HIV disease in association with APOL1 high-risk variants. HIV-immune complex disease is histologically the second most common diagnosis. With the introduction of antiretroviral therapy (ART), there has been a decline in the incidence of HIVAN, with an increasing prevalence of focal segmental glomerulosclerosis. Several studies have demonstrated overall improvement in kidney function with initiation of ART. Many antiretroviral medications are partially or completely eliminated by the kidney and require dose adjustment in CKD. HIV-positive patients requiring either hemo- or peritoneal dialysis, who are stable on ART, are achieving survival rates comparable to those of dialysis patients without HIV infection. Kidney transplantation has been performed successfully in HIV-positive patients; graft and patient survival is similar to that of HIV-negative recipients. Early detection of kidney disease by implementation of screening on diagnosis of HIV infection and annual screening thereafter will have an impact on the burden of disease, together with access to ART. Programs for prevention of HIV infection are essential.

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.

A review of renal disease in children with HIV infection.

Human immunodeficiency virus (HIV) infection continues to be a leading cause of morbidity and mortality. HIV-infected individuals are now surviving for a relatively longer period and this is because of easy accessibility to antiretroviral therapy these days. As a result, chronic disease-related complications are now being recognized more often. Kidney disease in HIV-infected children can vary from glomerular to tubular-interstitial involvement. We searched the database to identify various kidney diseases seen in HIV-infected children. We describe the epidemiology, pathogenesis, pathology, clinical and laboratory manifestations, management and outcome of commonly seen kidney disease in HIV-infected children. We also provide a brief overview of toxicity of antiretroviral drugs seen in HIV-infected children. Kidney involvement in HIV-infected children may arise because of HIV infection per se, opportunistic infections, immune mediated injury and drug toxicity. HIV-associated nephropathy is perhaps the most common and most severe form of kidney disease. Proteinuria may be a cost-effective screening test in the long-term management of HIV-infected children, however, there are no definite recommendations for the same. Other important renal diseases are HIV immune complex kidney disease, thrombotic microangiopathy, interstitial nephritis and vasculitis.

Race but not Hepatitis C co-infection affects survival of HIV+ individuals on dialysis in contemporary practice.

Individuals with HIV infection are at elevated risk of developing end-stage renal disease. However, their outcomes after starting chronic dialysis in the contemporary era of widespread antiretroviral therapy are not well described. Using detailed data from a national dialysis provider, we determined HIV status by administrative codes and antiretroviral medication prescriptions, with hepatitis C virus (HCV) co-infection status provided by routinely measured serology. The survival on dialysis among 5348 individuals in the HIV+ group and 1863 HIV+/HCV+ individuals to a HIV-/HCV- reference cohort was compared. Race significantly modified the effect of HIV and HIV/HCV infection on mortality. In a multivariable model, HIV infection was not associated with an increased risk of death among Caucasians (hazard ratio 1.03, 95% confidence interval 0.91-1.16) but HIV/HCV co-infection (1.48, 1.18-1.87) was. In the same model for non-Caucasians, both HIV infection (1.44, 1.37-1.52) and HIV/HCV co-infection (1.71, 1.60-1.84) were significantly associated with higher mortality. A secondary analysis using propensity scores yielded similar results. Median follow-up for the reference group was 645 days (interquartile range 230-1323), 772 days (276-1623) for the HIV+ group and 777 days (334-1665) for the co-infected group. Thus, in the contemporary era of widespread antiretroviral use, HIV infection remains associated with a significant reduction in dialysis survival for non-Caucasians while HIV/HCV co-infection is associated with impaired survival regardless of race or ethnicity. Hence, interventions to improve the care for these vulnerable populations are needed.

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.

Clinical characteristics and outcomes of HIV-associated immune complex kidney disease.

BACKGROUND: The pathogenesis and natural history of HIV-associated immune complex kidney disease (HIVICK) is not well understood. Key questions remain unanswered, including the role of HIV infection and replication in disease development and the efficacy of antiretroviral therapy (ART) in the prevention and treatment of disease. METHODS: In this multicentre study, we describe the renal pathology of HIVICK and compare the clinical characteristics of patients with HIVICK with those with IgA nephropathy and HIV-associated nephropathy (HIVAN). Poisson regression models were used to identify risk factors for each of these pathologies. RESULTS: Between 1998 and 2012, 65 patients were diagnosed with HIVICK, 27 with IgA nephropathy and 70 with HIVAN. Black ethnicity and HIV RNA were associated with HIVICK, receipt of ART with IgA nephropathy and black ethnicity and CD4 cell count with HIVAN. HIVICK was associated with lower rates of progression to end-stage kidney disease compared with HIVAN and IgA nephropathy (P < 0.0001). Patients with HIVICK who initiated ART and achieved suppression of HIV RNA experienced improvements in estimated glomerular filtration rate and proteinuria. CONCLUSIONS: These findings suggest a pathogenic role for HIV replication in the development of HIVICK and that ART may improve kidney function in patients who have detectable HIV RNA at the time of HIVICK diagnosis. Our data also suggest that IgA nephropathy should be viewed as a separate entity and not included in the HIVICK spectrum.

HIV-associated immune complex kidney disease.

The introduction in the late 20(th) century of combination antiretroviral therapy (cART) to treat patients infected with HIV has changed the natural history of the disease from an acute illness that rapidly culminates in death, to a chronic condition that can be managed with medications. Over the past decade the epidemiology of kidney disease in US patients infected with HIV has changed, perhaps because of the increased availability and use of cART. Patients with HIV infection exhibit unique immunologic characteristics, including immunodeficiency and dysregulation of immunoglobulin synthetic responses and T-cell function, which can result in glomerular immune complex deposition and subsequent kidney injury. This Review examines the differential diagnoses of HIV-associated immune complex kidney diseases (HIVICD), and discusses the clinical manifestations and mechanisms underlying their development. We address the issues associated with treatment, clinical outcomes, and research needs to enhance our ability to diagnose and optimally treat patients with HIVICD.

The effects of progressive-resisted exercises on muscle strength and health-related quality of life in persons with HIV-related poly-neuropathy in Zimbabwe.

Distal symmetrical poly-neuropathy (DSP) is a neurological complication associated with HIV/AIDS and stavudine (d4T) containing antiretroviral therapy. People with DSP experience pain, numbness and muscle weakness, which affect their quality of life (QOL). The purpose of this study was to establish the effect of a progressive-resisted exercise (PRE) intervention on health-related quality of life (HR-QOL) in people living with HIV/AIDS-related DSP. An assessor-blinded randomised controlled trial was conducted, with participants sourced from 10 clinics with HIV services, the family care clinic at Wilkins Hospital and 2 large hospitals in Harare, Zimbabwe. A 12-week PRE intervention was conducted twice weekly for 80 participants, while the control group with 80 participants continued with usual daily activities. The main outcome variable was HR-QOL for which we controlled for demographic and clinical measures in generalised estimating equation population-averaged models. Data were summarised and analysed using an intention to treat analysis approach using the Stata v10 program. Mean age of participants was 42.2 years (SD = 8.5). While d4T was used by 59% (n = 94), an equal proportion of the participants also had moderate to severe neuropathy. PRE was found to significantly improve HR-QOL in the intervention group based on the mean difference between the intervention group mean change and the mean change in the control group (F ratio 4.24; p = .04). This study established that PREs have positive effects on HR-QOL for people living with HIV/AIDS-related DSP.

The National NeuroAIDS Tissue Consortium (NNTC) Database: an integrated database for HIV-related studies.

We herein present the National NeuroAIDS Tissue Consortium-Data Coordinating Center (NNTC-DCC) database, which is the only available database for neuroAIDS studies that contains data in an integrated, standardized form. This database has been created in conjunction with the NNTC, which provides human tissue and biofluid samples to individual researchers to conduct studies focused on neuroAIDS. The database contains experimental datasets from 1206 subjects for the following categories (which are further broken down into subcategories): gene expression, genotype, proteins, endo-exo-chemicals, morphometrics and other (miscellaneous) data. The database also contains a wide variety of downloadable data and metadata for 95 HIV-related studies covering 170 assays from 61 principal investigators. The data represent 76 tissue types, 25 measurement types, and 38 technology types, and reaches a total of 33,017,407 data points. We used the ISA platform to create the database and develop a searchable web interface for querying the data. A gene search tool is also available, which searches for NCBI GEO datasets associated with selected genes. The database is manually curated with many user-friendly features, and is cross-linked to the NCBI, HUGO and PubMed databases. A free registration is required for qualified users to access the database.

HIV-associated nephropathies: epidemiology, pathology, mechanisms and treatment.

HIV is a highly adaptive, rapidly evolving virus, which is associated with renal diseases including collapsing glomerulopathy-the classic histomorphological form of HIV-associated nephropathy. Other nephropathies related to viral factors include HIV-immune-complex kidney disease and thrombotic microangiopathy. The distribution of HIV-associated kidney diseases has changed over time and continues to vary across geographic regions worldwide. The reasons for this diversity are complex and include a critical role of APOL1 variants and possibly other genetic factors, disparities in access to effective antiviral therapies, and likely other factors that we do not yet fully understand. The mechanisms responsible for HIVAN, including HIV infection of podocytes and tubular epithelial cells, the molecules responsible for HIV entry, and diverse mechanisms of cell injury, have been the focus of much study. Although combined antiretroviral therapy is effective at preventing and reversing HIVAN, focal segmental glomerulosclerosis, arterionephrosclerosis and diabetic nephropathy are increasingly common in individuals who have received such therapy for many years. These diseases are associated with metabolic syndrome, obesity and premature ageing. Future directions for HIV-related kidney disease will involve regular screening for drug nephrotoxicity and incipient renal disease, as well as further research into the mechanisms by which chronic inflammation can lead to glomerular disease.

Predictors of HIV-associated nephropathy.

Renal disease accounts for significant morbidity and mortality in patients with HIV-1 infection. HIV-associated nephropathy (HIVAN) is an important cause of end stage renal disease in this population. Although multiple genetic, clinical, and laboratory characteristics such as Apolipoproetin-1 genetic polymorphism, high viral load, low CD-4 count, nephrotic range proteinuria, and increased renal echogenicity on ultrasound are predictive of HIVAN, kidney biopsy remains the gold standard to make the definitive diagnosis. Current treatment options for HIVAN include initiation of combined active antiretroviral therapy, blockade of the renin-angiotensin system, and steroids. In patients with progression of HIVAN, renal transplant should be pursued as long as their systemic HIV infection is controlled.

[Case of serious HIV-associated nephropathy resulting in the introduction of hemodialysis].

A previously healthy 46-year-old black man visited the other hospital because of fever, appetite loss and nausea. Renal dysfunction, liver injury, and a highly markedly elevated LDH level were found. Abdominal CT demonstrated enlarged liver, spleen, kidney and lymph nodes. Human immunodeficiency virus (HIV) was serologically positive. His serum BUN, creatinine and potassium were 74.9 mg/dL, 11.78 mg/dL, and 5.6 mEq/L, respectively. After admission, anuria persisted and the progression of renal failure continued despite various treatment methods, necessitating the introduction of maintenance hemodialysis(HD). A kidney biopsy was performed to confirm classical HIV-associated nephropathy (HIVAN). Antiretroviral therapy (ART) was started. Although urine was transiently excreted, HD could not be discontinued. It has been reported that HIVAN is too difficult to treat and that kidney dysfunction seldom recovers. HIVAN is well-known to occur frequently in black HIV-infected patients. However, in Japan, there have been only a few reports describing patients with serious HIVAN and renal failure necessitating HD. We present here a very rare case with HIVAN, with reference to some recent findings.

Kidney disease in HIV-infected patients.

The introduction of highly active antiretroviral therapy (HAART) has reduced mortality and improved life expectancy of HIV-positive patients. However, increased survival is associated with increased prevalence of comorbidities, such as cardiovascular disease, hepatic and renal disease. Kidney disease, including HIV-associated nephropathy, acute renal failure and chronic kidney disease, represents one of the main causes of morbidity and mortality, especially if associated to other risk factors, i.e. hypertension, diabetes, older age, black race and hepatitis C coinfection. Careful evaluation of renal function may help identifying kidney disease in its early stages. In addition, proper management of hypertension and diabetes is recommended. Even if HAART has changed the natural course of HIV-associated nephropathy, reducing the risk of End-stage Renal Disease (ERDS), some antiretroviral regimens have been related with the development of acute or chronic kidney disease. Further studies are needed to optimize the management of renal disease among HIV-infected patients.

HIV-associated nephropathy (HIVAN): a short review of different authors.

Human immunodeficiency virus associated nephropathy (HIVAN) is clinically and morphologically a distinctive type of renal parenchymal disorder. It is presented in an HIV-seropositive individual by proteinuria and progressive renal insufficiency, usually without oedema or hypertension. Renal biopsy most commonly reveals a collapsing form of focal segmental glomerulosclerosis with marked proliferation of glomerular podocytes and tubular microcystic dilatation. These characteristic changes are attributed to incorporation of DNA and mRNA of human immunodeficiency virus type 1 into the renal parenchymal cells. Newly introduced highly active anti-retroviral therapy (HAART) has significantly reduced the incidence of HIVAN in the recent years. The HAART has been found to retard and revert the progression of renal insufficiency towards end-stage renal disease, and to increase survival of the patient. Therefore a renal biopsy should be performed in all suspected patients for definitive diagnosis of HIVAN and better patient management.

End-stage renal disease and dialysis in HIV-positive patients: observations from a long-term cohort study with a follow-up of 22 years.

OBJECTIVES: Renal disease is a common and serious complication in HIV-infected patients. METHODS: A retrospective cohort analysis for the period 1989-2010 was carried out to determine the prevalence, incidence and risk factors for end-stage renal disease (ESRD). ESRD was defined as initiation of renal replacement therapy. Three time periods were defined: 1989-1996 [pre-highly active antiretroviral therapy (HAART)], 1997-2003 (early HAART) and 2004-2010 (late HAART). RESULTS: Data for 9198 patients [78.2% male; 88.9% Caucasian; cumulative observation time 68 084 patient-years (PY)] were analysed. ESRD was newly diagnosed in 35 patients (0.38%). Risk factors for ESRD were Black ethnicity [relative risk (RR) 5.1; 95% confidence interval (CI) 2.3-10.3; P < 0.0001], injecting drug use (IDU) (RR 2.3; 95% CI 1.1-4.6; P = 0.02) and hepatitis C virus (HCV) coinfection (RR 2.2; 95% CI 1.1-4.2; P = 0.03). The incidence of ESRD decreased in Black patients over the three time periods [from 788.8 to 130.5 and 164.1 per 100 000 PY of follow-up (PYFU), respectively], but increased in Caucasian patients (from 29.9 to 41.0 and 43.4 per 100 000 PYFU, respectively). The prevalence of ESRD increased over time and reached 1.9 per 1000 patients in 2010. Mortality for patients with ESRD decreased nonsignificantly from period 1 to 2 (RR 0.72; P = 0.52), but significantly from period 1 to 3 (RR 0.24; P = 0.006), whereas for patients without ESRD mortality decreased significantly for all comparisons. ESRD was associated with a high overall mortality (RR 9.9; 95% CI 6.3-14.5; P < 0.0001). CONCLUSION: As a result of longer survival, the prevalence of ESRD is increasing but remains associated with a high mortality. The incidence of ESRD declined in Black but not in Caucasian patients. IDU and HCV were identified as additional risk factors for the development of ESRD.