Continuing Education Activity

Human immunodeficiency virus (HIV)-associated nephropathy is an aggressive condition that requires prompt diagnosis to prevent permanent damage to renal function. While the advent of combined antiretroviral therapy and early diagnosis of HIV has made this condition rare, it is important to understand the repercussions it could have, especially in those with poor access to healthcare. This activity reviews the evaluation and treatment of HIV-associated nephropathy and highlights the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Identify the etiology of HIV-associated nephropathy.
• Describe the appropriate history, physical, and evaluation of HIV-associated nephropathy.
• Outline the treatment and management options available for HIV-associated nephropathy.
• Review interprofessional team strategies for improving care coordination and communication to advance the care of HIV-associated nephropathy treatment and improve outcomes.

Introduction

The human immunodeficiency virus (HIV) is a rapidly evolving virus that has been associated with renal disease since the early days of the HIV epidemic. Classically associated with collapsing focal segmental glomerulosclerosis, direct HIV-related nephropathy can also manifest as HIV-immune-complex kidney disease and thrombotic microangiopathy. In recent years, with the advent of combination antiretroviral therapy and effective diffusion of these medications, patients are living longer lives without classic manifestations of the disease. Currently, disorders associated with nephrotoxicity of certain HIV therapies appear to be more prevalent, as well as a surge in non-infectious comorbidities, such as diabetes or hypertension, as etiologies of nephropathy in people living with HIV (PLWHIV). Renal disease remains one of the major causes of mortality in patients infected with HIV, with a six-fold increase in mortality for those suffering from acute kidney injury (AKI) and chronic kidney disease (CKD). Furthermore, since HIV can infect and replicate within renal epithelial cells, a full virologic cure may only be feasible with complete eradication of the viral reservoir in the kidney as this compartment appears to act separately from the blood.[1][2][3][4][5][6]

Etiology

There is a diverse range of renal pathology in PLWHIV, such as lesions resulting directly from intrarenal HIV gene expression and injuries secondary to comorbidities, drug-induced nephrotoxicity, and immune dysregulation, among others. Renal disease associated with HIV infection is primarily a glomerular dominant disease that is further classified into two main categories: podocytopathies and immune complex-mediated disease. The major subtypes of podocytopathy that have been described in the setting of HIV infection are classic HIV-associated nephropathy (HIVAN), focal segmental glomerulosclerosis not otherwise specified, and the far less common, minimal change disease and diffuse mesangial hypercellularity. These are characterized by extensive podocyte foot process effacement and proteinuria mediated by direct HIV infection of renal epithelial cells, intrarenal viral gene expression, and dysregulation of host genes. Several forms of immune complex-mediated disease have been reported in PLWHIV. The causal relation is not well established yet, and secondary causes should be sought out in cases of post-infectious glomerulonephritis, lupus-like nephritis, IgA nephropathy, membranous nephropathy, and membranoproliferative glomerulonephritis, among others.[3][7][8]

Epidemiology

HIV-associated nephropathy incidence peaked in the mid-1990s, being reported in 3.5%–10% of the HIV-infected population in the USA. It was primarily in individuals of African descent, but prevalence has been declining as a result of the widespread use of combined anti-retroviral treatments.[9]

Pathophysiology

HIV-Associated Nephropathy

The expression of HIV-1 genes in the kidney epithelial cells is required for the development of HIVAN. The mechanism by which HIV infects renal epithelial cells remains unclear. The classical receptors necessary for entry of the virus into T cells and macrophages are absent from renal cells. Various studies have shown that macrophages and lymphocytes appear to be vectors necessary for renal epithelial cell transmission of HIV. Among these are CD209 antigen (DC-SIGN), which mediates HIV infection of dendritic cells, and lymphocyte antigen 75 (DEC-205), which may directly contribute to infection of renal tubular epithelial cells. Polymorphisms in APOL1 result in an increased risk of HIVAN. However, the mechanism by which these variations cause HIVAN is yet to be elucidated. It appears likely that the infection of renal tubular epithelial cells by HIV is mediated via transfer from leukocytes. Phagocytosis of apoptotic CD4+ T cells has also been proposed as a possible mechanism by which HIV accesses renal cells. The HIV proteins Vpr and Tat circulate in plasma and through proteoglycans, and lipid rafts have access to podocytes.[3][5][6]

HIV-Associated Immune Complex Kidney Disease

Many of the glomerular lesions associated with HIV-associated immune complex kidney disease (HIVICK) are routinely caused by co-infection with hepatitis B and C. Studies performed before the advent of combined antiretroviral therapy showed anti-HIV antibodies which may form immune complexes that could result in glomerulonephritis, but the mechanism and relevance in the post-antiretroviral era are unknown.[5][10]

HIV-Associated Thrombotic Microangiopathy

Thrombotic microangiopathy is a well-known complication of late-stage HIV/AIDS (acquired immunodeficiency syndrome) but its incidence has decreased dramatically since the arrival of combined antiretroviral treatments. While its pathogenesis remains to be elucidated, it is postulated that the source of endothelial injury is the exposure to circulating viral proteins combined with other factors such as medications, proinflammatory molecules, and antiphospholipid antibodies.[1][10]

Histopathology

HIV-associated nephropathy is defined as a collapsing glomerulopathy and associated tubulointerstitial disease, which may include tubular microcysts and inflammation of the interstitium. Diffuse effacement of podocyte foot process and endothelial tubular inclusions are mainstays when examined by electron microscopy. Staining for IgM, C3, and C1q in collapsed segments and mesangial areas is common by immunofluorescence.[6][7]

History and Physical

HIV-associated nephropathy classically presents with a swift decline in GFR and proteinuria in the nephrotic range. Other manifestations of nephropathy, such as peripheral edema of the lower extremities and hypertension, are uncommon in this population. Since concomitant conditions and infections are likely in this population, the importance of ruling out other etiologies should be emphasized.[4][11][12]

Evaluation

Guidelines from the HIV Medicine Association of the Infectious Diseases Society of America state that screening for HIV nephropathy in HIV positive patients should include serum creatinine and estimated glomerular filtration rate (GFR) along with urinalysis or a quantitative measure of proteinuria at baseline when antiretroviral therapy (ART) is initiated or changed, and at least twice a year in stable patients infected with HIV. Imaging modalities, such as ultrasonography of the kidneys, has been evaluated as a possible non-invasive test for the diagnosis of HIVAN. Studies have shown that high scores of renal echogenicity were strong predictors for HIVAN, while low scores could effectively rule it out. While this appears to be useful in specific settings, most of the patients suffering from HIVAN have echogenicity scores that fall between those two values. A kidney biopsy is often the only means of achieving a definitive diagnosis. Indications for biopsy remain the same as for the general population. The decision to perform a kidney biopsy should take into consideration the clinical presentation, the likelihood of alternate diagnosis, the therapeutic options, and the risks associated with the procedure.[3][13]

Currently, combination antiretroviral therapy (cART) induced nephropathy is a far more common disease than HIVAN. Differentiating patients with HIVAN versus cART induced nephropathy is important, as management is different. Besides history and physical examination findings, patients with HIVAN present with CD4 count <200 cells/mm, viral load >400 copies/mL, a rapid decline in renal function, proteinuria >300 mg/24h, hyaline or proteinaceous casts on urinalysis, and large-sized kidneys with intense cortical echogenicity. In contrast, cART induced nephropathy presents in patients with CD4 count >200 cells/mm, viral load <400 copies/mL, proteinuria <30 mg/24h, an indolent decline in renal function, hematuria or leukocyturia, needle or rod-like crystals on urine microscopy and unremarkable ultrasound findings.[13][14]

Treatment / Management

Since HIVAN is associated with a high risk for progression to end-stage renal disease (ESRD) and increased mortality, treatment should not be delayed. Combined antiretroviral therapy continues to be the mainstay of treatment for HIVAN, as it has been shown to reduce the likelihood of progression into ESRD. Renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) is also important since it has been shown to improve renal survival and should be considered as an adjunct to cART in HIVAN. In patients with refractory renal impairment after cART and RAAS blockade treatment, steroids can be added as an adjunct, but data supporting them as primary treatment is weak, and the side effect profile is broad. It is important to adjust cART therapy to renal function as some have been shown to directly affect renal function, such as tenofovir, atazanavir, and indinavir. In those who progress to ESRD, renal replacement therapy remains the mainstay of management, and renal transplantation can be considered as the evidence demonstrates it is effective in patients with controlled HIV.[9][14][15]

Differential Diagnosis

• HIV-associated immune complex kidney disease
• Membranoproliferative glomerulonephritis (associated with concurrent hepatitis C infection)
• Amyloidosis
• Minimal change disease
• Postinfectious glomerulonephritis
• Thrombotic microangiopathy
• Diabetic nephropathy
• Immunoglobulin A nephropathy
• Membranous glomerulopathy

Prognosis

Before the advent of combined antiretroviral therapy, HIVAN was an aggressive disease that resulted in rapid progression to end-stage renal disease within 2-4 months. Currently, the prognosis is more favorable. However, patients with HIVAN consistently do worse than patients with other causes of renal disease.[4]

Complications

The mainstay complication of HIVAN is a progression into CKD, and subsequently, ESRD requiring renal replacement therapy. Other complications include hypertension and lower extremity edema, which are far less common.[3][4]

Deterrence and Patient Education

HIV-associated nephropathy is an aggressive disease that will result in end-stage renal disease if no treatment is initiated. Patients should be encouraged to be compliant with antiretroviral medications and to follow with their primary care clinician and nephrologist on a regular basis.

Pearls and Other Issues

HIVAN is classically manifested as focal segmental glomerulosclerosis. The natural course of the condition is rapid progression to end-stage renal disease in 2-4 months. Combined antiretroviral therapy is the mainstay treatment because it hastens progression and improves renal survival. Currently, other etiologies of kidney disease, such as hypertension and diabetes, are more common than HIVAN due to the advent of cART and improved survival in patients infected with HIV.

Enhancing Healthcare Team Outcomes

Due to the aggressive nature of HIVAN, prompt diagnosis and treatment should be made in cases of suspected disease. An interprofessional team approach will improve patient outcomes. The team should include a primary care provider, a nephrologist, and an infectious disease specialist. Frequent renal function testing as per HIV association guidelines should be followed in every patient with HIV. Biopsy should be considered after considering alternative diagnoses and the risks associated with the procedure. An interventional radiologist and pathologist will need to be a part of the team at this point. CD4 count and viral load should be measures to take into consideration for the initiation of cART in patients with HIVAN.