Incidence Of HIV-associated Nephropathy Research Articles

Mechanisms of Proteinuria in HIV.

Proteinuria is common in the setting of HIV infection, and may reflect comorbid kidney disease, treatment-related nephrotoxicity, and HIV-related glomerular diseases. The mechanisms of podocyte and tubulointerstial injury in HIV-associated nephropathy (HIVAN) have been the subject of intense investigation over the past four decades. The pathologic contributions of viral gene expression, dysregulated innate immune signaling, and ancestry-driven genetic risk modifiers have been explored in sophisticated cellular and whole animal models of disease. These studies provide evidence that injury-induced podocyte dedifferentiation, hyperplasia, cytoskeletal dysregulation, and apoptosis may cause the loss of glomerular filtration barrier integrity and slit diaphragm performance that facilitates proteinuria and tuft collapse in HIVAN. Although the incidence of HIVAN has declined with the introduction of antiretroviral therapy, the collapsing FSGS lesion has been observed in the context of other viral infections and chronic autoimmune disorders, and with the use of interferon-based therapies in genetically susceptible populations. This highlights the fact that the lesion is not specific to HIVAN and that the role of the immune system in aggravating podocyte injury warrants further exploration. This review will summarize our progress in characterizing the molecular mechanisms of podocyte dysfunction in HIVAN and other forms of HIV-associated kidney disease.

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.

Management of Renal Disease: utility of a joint HIV-renal clinic

Although there has been a decrease in the incidence of HIV-associated nephropathy, the incidence of chronic kidney disease (CKD) is increasing in patients attending HIV clinics. Traditional risk factors for CKD, including diabetes, hypertension and coinfection with hepatitis C virus, are overrepresented in this population, making it difficult to distinguish the contribution of HIV infection 1. HIV-infected patients are at risk of renal dysfunction caused by HIV and by antiretroviral treatment (ART) toxicity. In particular, tenofovir disoproxil fumarate (TDF) has been associated with proximal renal tubular dysfunction 2. In 2014 locally in Brighton we had a cohort of 2150 HIV-infected patients, 90% of whom were on ART with 910 of 1935 (47.0%) on regimens including TDF. In addition to using a written protocol for monitoring renal function in patients on antiretrovirals (ARVs) and a standardized operating policy for investigation of abnormal blood tests and urinalysis, we run a ‘one-stop shop’ HIV-renal specialist clinic with an HIV physician and renal physician working together seeing referrals from the general HIV clinic. This study aimed to investigate the utility of this clinic and to describe renal disease in this cohort. We reviewed all patient records of patients seen in a specialist HIV-renal clinic between 2012 and 2014. Demographics, HIV history, number of visits, the indication for referral and outcome information were collected using a standardized proforma. Sixty-five patients, with a median age of 51 years (28–88 years) and a median duration of HIV infection of 163 months (20–335 months), were seen. Forty-two were taking TDF for a mean of 55.8 months (9–122 months). A total of 42 of 65 patients were reviewed once with a median number of visits of 1 (1–4). There were 98 appointments, 54 of which were virtual. The did-not-attend (DNA) rate was 11.4%. Referred patients were categorized as having: proteinuria on TDF (38 of 65 patients; 59%), proteinuria not on TDF (12 of 65 patients; 18%) and raised creatinine without proteinuria (15 of 65 patients; 23%). Of the 38 patients on TDF with proteinuria, five (13.2%) had TDF toxicity diagnosed and TDF was discontinued immediately, and 27 continued with close monitoring with a further seven subsequently discontinuing; the total number discontinuing was 12 of 38 (32%). Addition or up-titration of medications for poorly controlled hypertension was the commonest intervention overall in the joint HIV-renal clinic (23 of 65 patients; 35.4%), in particular in the non-TDF proteinuria group (eight of 12 patients; 66.7%). Renal calculi were a frequent contributor to renal dysfunction and four of 65 patients (6%) had a new glomerular diagnosis after undergoing renal biopsy [two had focal segmental glomerulosclerosis, one had immunoglobulin A (IgA) nephropathy and one had glomerulonephritis with granulomata]. In four patients (6%), the creatinine rise was attributed to nonsteroidal anti-inflammatory drug (NSAID), creatine or protein supplement usage. TDF toxicity was the commonest reason for referral but only a minority of referred patients (13.2%) needed to discontinue immediately. Optimizing blood pressure control was the most frequent outcome, suggesting that this is an underappreciated priority among HIV physicians.

HIV and chronic kidney disease.

Chronic kidney disease (CKD) is a frequent complication of HIV infection, occurring in 3.5 – 48.5%, and occurs as a complication of HIV infection, other co-morbid disease and infections and as a consequence of therapy of HIV infection and its complications. 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 the second most common diagnosis obtained from biopsies of patients with HIV-CKD. CKD is mediated by factors related to the virus, host genetic predisposition and environmental factors. The host response to HIV infection may influence disease phenotype through activation of cytokine pathways. 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 the overall improvement in kidney function when initiating ART for HIV CKD. Progression to end stage kidney disease has been reported to be more likely when high grade proteinuria, severely reduced eGFR, hepatitis B and/C co-infection, diabetes mellitus, extensive glomerulosclerosis, and chronic interstitial fibrosis are present. Improved renal survival is associated with use of renin angiotensin system blockers and viral suppression. Many antiretroviral medications are partially or completely eliminated by the kidney and require dose adjustment in CKD. Certain drug classes, such as the protease inhibitors and the non-nucleoside reverse transcriptase inhibitors, are metabolized by the liver and do not require dose adjustment. HIV-infected 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-infected patients; graft and patient survival appears to be similar to that of HIV-uninfected 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 to those who require it. Programs for prevention of HIV infection are essential to prevent this lethal disease.

End-Stage Renal Disease and HIV: Where We Are Now

Although the incidence of HIV-associated nephropathy has declined since the advent of potent combination antiretroviral therapy (ART), HIV-infected

Expression of HIV transgene aggravates kidney injury in diabetic mice

With the widespread use of combination antiretroviral agents, the incidence of HIV-associated nephropathy has decreased. Currently, HIV-infected patients live much longer and often suffer from comorbidities such as diabetes mellitus. Recent epidemiological studies suggest that concurrent HIV infection and diabetes mellitus may have a synergistic effect on the incidence of chronic kidney disease. To address this, we determined whether HIV-1 transgene expression accelerates diabetic kidney injury using a diabetic HIV-1 transgenic (Tg26) murine model. Diabetes was initially induced with low-dose streptozotocin in both Tg26 and wild-type mice on a C57BL/6 background, which is resistant to classic HIV-associated nephropathy. Although diabetic nephropathy is minimally observed on the C57BL/6 background, diabetic Tg26 mice exhibited a significant increase in glomerular injury compared with nondiabetic Tg26 mice and diabetic wild-type mice. Validation of microarray gene expression analysis from isolated glomeruli showed a significant upregulation of proinflammatory pathways in diabetic Tg26 mice. Thus, our study found that expression of HIV-1 genes aggravates diabetic kidney disease.

Recent Developments in HIV-Related Kidney Disease

Although kidney disease has been a recognized complication of HIV infection since the beginning of the HIV epidemic, its epidemiology, underlying causes and treatment have evolved in developed countries where HAART has been widely available. HIV-associated nephropathy and HIV immune complex-mediated kidney disease were the prominent renal diagnoses in the earlier period of the HIV epidemic. While HIV immune complex-mediated kidney disease remains a common finding among HIV-infected individuals with kidney disease, the incidence of HIV-associated nephropathy has been diminishing in developed countries. The role of the metabolic effects of long-term HAART exposure and nephrotoxicity of certain antiretroviral medications on the development and progression of chronic kidney disease is now of increasing concern. The long-term clinical implications of acute kidney injury among HIV-infected persons are increasingly recognized. Kidney disease in HIV-infected persons continues to be a major risk factor for morbidity and mortality in this patient population; therefore, early recognition and treatment of kidney disease are imperative in lessening the impact of kidney disease on the health of HIV-infected individuals. This review focuses on recent developments and ongoing challenges in the understanding, diagnosis and management of HIV-related kidney disease.

Virologic Suppression and HIV-Associated Nephropathy

HIV-associated nephropathy, which is more common in blacks than in whites, is often seen in the setting of advanced HIV disease and lack of virologic suppression. In this retrospective study, conducted at eight HIV clinics in the U.K., investigators determined the prevalence and incidence of HIV-associated nephropathy — and then evaluated the association between virologic suppression and renal outcomes. Of the 16,834 patients who were seen between January 1998 and December 2004, 61 had HIV-associated nephropathy; all were black (79% African; 21% British or Caribbean). …

Relapse of HIV-associated nephropathy after discontinuing highly active antiretroviral therapy

F.H., a 53-year-old African American woman presented to her primary care provider with acute renal failure (creatinine 2.7 mg/dl from baseline of 1.3 mg/dl) and proteinuria (1.6 g of protein per 24 h). Her past medical history was significant only for hypertension and asthma. Evaluation revealed a positive HIV antibody and a CD4 cell count of 281 cells/μl. F.H. was started on antiretroviral therapy with zidovudine, and a renal biopsy demonstrated glomerular capillary loop collapse and a tubulointerstitial lymphocyte infiltrate with cystically dilated tubules and atrophy consistent with HIV-associated nephropathy (HIVAN). In addition to her antiretroviral therapy she was treated with an angiotensin-converting enzyme inhibitor and a course of corticosteroids. Her creatinine level peaked at 4.6 mg/dl and proteinuria was at approximately 3 g per 24 h. Over the next 3 years her creatinine and proteinuria levels stabilized as she was treated with zidovudine and lamivudine with a relatively suppressed viral load and rising CD4 cell count (see Fig. 1). In March 1999, she was started on HAART with stavudine, didanosine and efavirenz resulting in complete viral suppression and a rise in the CD4 cell count to approximately 900 copies/μl for 2 years. During this period the creatinine level declined to 1.8 mg/dl and urinary protein dropped to 500 mg per 24 h. In August 2001, F.H. discontinued HAART as a result of the side effects of therapy. Her viral load quickly rose to over 300 000 copies/ml and her renal function worsened, with a creatinine level of 3.8 mg/dl in May 2002. A renal ultrasound revealed small echogenic kidneys, consistent with chronic disease, and renal biopsy confirmed recurrent active HIVAN. F.H. was again treated with corticosteroids and HAART, now consisting of zidovudine/lamivudine/abacavir and efavirenz. Over the next 3 years her viral load was fully suppressed on this regimen and her renal function, although severely compromised, has stabilized (estimated glomerular filtration rate 15 ml/min per 1.73 m2) avoiding the need for renal replacement therapy. In addition, there was a dramatic decline in proteinuria from an estimated 5 g to 1 g per 24 h.Fig. 1: Serum creatinine (mg/dl) and urine protein to creatinine ratio (grams protein/grams creatinine) versus time, during therapy with HAART. The upper bars indicate the antiretroviral treatment regimen during the corresponding time intervals. The fluctuation in HIV viral load in relation to time and treatment is indicated in the upper graph. CD4 cell count (cells/ml) at various points in time is indicated numerically below the treatment bars. The lower graph indicates serum creatinine (▵) and urine protein to creatinine ratios (□) versus time and in relation to the ongoing treatment indicated in the upper treatment bars. ABC, Abacavir; ddI, didanosine; D4T, stavudine; EFV, efavirenz; 3TC, lamivudine; ZDV, zidovudine.Epidemiological studies have shown a correlation between increasing HIV viral load, decreasing CD4 cell count and the occurrence of proteinuria and renal failure [1], as well as a reduction in the incidence of HIVAN in patients treated with HAART [2]. Previous case reports have demonstrated a reversal of acute renal failure and histological changes on biopsy after short courses of antiretroviral therapy [3]. Several observational cohort studies have demonstrated a decreased need for renal replacement therapy for patients treated with antiretroviral therapy compared with those not so treated [4–6]. This case supports the hypothesis that HIVAN can be treated by the suppression of viral replication with HAART, and when initiated early may remove the need for renal replacement therapy and provide long-term stabilization of disease. Unlike the previous reported cases, this case suggests a risk of relapse of disease after discontinuing HAART. This suggests that a history of HIVAN alone may be an indication for indefinite HAART, even with an adequate CD4 cell count and despite mild to moderate side effects.

Antiretroviral therapy and the kidney: balancing benefit and risk in patients with HIV infection

The widespread introduction of highly active antiretroviral therapy (HAART) has revolutionised the treatment and course of HIV infection, with complications of chronic HIV infection and HAART playing an increasingly important role in morbidity and mortality. Both HIV infection and HAART have been associated with the development of acute and chronic kidney disease. The incidence of HIV-associated nephropathy, the classic kidney disease of HIV, reached a plateau following the introduction of HAART, consistent with the pathogenic role of direct viral infection of the kidney. At the same time, antiretroviral agents and related therapies have demonstrated a range of nephrotoxic effects, including crystal-induced obstruction, lactic acidosis, tubular toxicity, interstitial nephritis and electrolyte abnormalities. This article reviews the impact of HAART on the epidemiology of HIV-related kidney disease, the potential nephrotoxicity of specific antiretroviral agents and related medications, and guidelines for monitoring kidney function in HAART-treated patients.

Recent progress in HIV-associated nephropathy.

The classic kidney disease of HIV infection, HIV-associated nephropathy (HIVAN), is an aggressive form of collapsing focal segmental glomerulosclerosis with accompanying tubular and interstitial lesions. HIVAN was first described among African-Americans and Haitian immigrants with advanced HIV disease, an early suggestion of a strong genetic association. This genetic susceptibility was recently linked to polymorphisms on chromosome 22 in individuals of African descent. The association with advanced HIV infection and evidence from HIV-transgenic mice suggested the possibility that HIV directly infects the kidney and that specific HIV gene expression induces host cellular pathways that are responsible for HIVAN pathogenesis. Although combination antiretroviral therapy has substantially reduced the impact of HIVAN in the United States, continued growth of the HIV epidemic in susceptible African populations may have important public health implications. This article reviews recent progress in the pathogenesis...