One of the earliest descriptions of human immunodeficiency virus (HIV)-associated nephropathy (HIVAN), published in 1984, described a focal segmental glomerulosclerosis of unclear aetiology.(1)In the subsequent period leading up to the introduction of highly active antiretroviral therapy (HAART), HIVAN was recognized as a major cause of HIV-related mortality, particularly among those of Black race.(2)The condition was frequently accompanied by severe proteinuria, and acute kidney injury (AKI) leading rapidly to end-stage renal disease (ESRD) and death.(3)
In the HAART era, the risk of ESRD in HIV patients has diminished substantially in both Blacks and Whites.(4-5)Individuals of African descent, however, still remain at greater risk for HIVAN and other forms of kidney disease.(6)This is attributed to a large extent to a genetic susceptibility created by variants of the APOL1 gene on chromosome 22,(7)which are uniformly present in those with HIVAN, a histopathological entity distinct from other forms of CKD that is best confirmed with biopsy. The variants, or polymorphisms, also appear to explain the increased risk of ESRD in HIV-negative Blacks relative to HIV-negative Whites,(8), and may explain the far more rapid deterioration of renal function in HIV-positive Blacks when compared to HIV-positive Whites.(5)There have been no randomized trials to confirm the ability of HAART to prevent HIVAN, but retrospective analyses indicate that HIVAN is an uncommon complication in patients who begin HAART prior to severe immune deficiency and who maintain a HIV viral load <400 copies/mL.(9)HIVAN is now generally confined to patients who reach an advanced stage of immunodeficiency before antiretroviral therapy is initiated, but current treatment strategies, as discussed below, may prevent progression to ESRD. In those evolving to ESRD kidney transplantation may allow a dialysis free, long term survival.(10)
Despite the diminished likelihood of HIVAN in the HAART era, the risk of renal disease in patients with HIV infection is expected to increase in aging HIV-infected individuals for a number of reasons. The presence of microalbuminuria, a precursor to more severe renal disease, is up to five-times higher than in non-HIV controls after multivariate adjustment.(11)Unlike HIVAN, renal disease in the era of HAART is associated with indolent rather than acute pathological processes, even though, ultimately, it may be no less life-threatening. In the assessment of renal function obtained in 20,132 HIV-infected patients, baseline estimated glomerular filtration rate (eGFR) in the post-HAART era was a strong predictor of mortality.(12) (Fig. 1). This is not surprising due to the numerous studies in the non-HIV infected showing similar outcomes.
In the growing literature documenting acceleration of age-related processes, the kidney can be both directly and indirectly affected (13). For example, type 2 diabetes mellitus, which is a major risk factor for renal impairment, is four times more prevalent in patients with HIV relative to an age-matched population. (14)The prevalence of hypertension, another risk factor for renal impairment, is up to three times higher.(15)Hepatitis C virus (HCV), which can also impair renal function, is far more common in individuals with HIV than in those who are not infected.(16)
In addition, it is now clear that several antiretroviral therapies also increase the risk of chronic kidney disease (CKD). Often, the relative increase in risk is subtle, but antiretroviral therapies must be taken indefinitely, possibly producing risk from a cumulative effect. Although there may be no goal more important in the treatment of HIV than sustaining a low viral load, selecting an agent that poses a low risk of renal impairment may be particularly important to those who already have risk factors for renal disease or established renal impairment.(17)
For the clinician, it is important to recognize the growing problem of CKD in aging individuals with HIV infection and to consider a broad range of presentations and aetiologies.(18)Importantly, many of these aetiologies are the same as those encountered in a non-HIV-infected population but occur at a younger age with a greater propensity for life-threatening complications over a shorter period of time. (Table 1).
The HIVAN of the pre-HAART era and the CKD common to aging individuals with controlled HIV infection are generated by very different pathological events. HIVAN has been attributed to localized HIV infection of renal glomerular and tubular epithelial cells, which produces glomerulosclerosis and tubulointerstitial scarring.(19-20)HIV infection of renal epithelial cells thereby drives impairment of glomerular filtration by directly disturbing cell functions. HIV-specific immune complex glomerulonephritis and HIV-related thrombotic microangiopathy, which do not occur more frequently in Blacks, are less common renal diseases associated HIV.(7)
To understand the recent and ongoing growth of renal disease in individuals with HIV infection, it is important to recognize that CKD is a common condition in the absence of HIV infection, and that overall rates are increasing. Likely to be at least partly due to the growing problem of obesity and its associated pathology, particularly diabetes,(21)the rising rates of CKD may also be attributed to the demographic shift that is increasing the median age in Canada and elsewhere.(22)Similar trends, particularly the aging of individuals with HIV, explain the rising rate of CKD in individuals infected with HIV.
However, the HIV population has additional risks, which not only include a high prevalence of diseases that may adversely affect renal function, such as hepatitis C infection, but a relatively high risk of exposure to nephrotoxic drugs, which includes antiretrovirals, illicit drugs such as cocaine, as well as antibiotics such as gentamicin and amphotericin.(23). Patients with HIV infection may not have any greater risk of exposure to other agents associated with nephrotoxicity, such as non-steroidal anti-inflammatory drugs (NSAIDs), but they may be more likely to develop renal complications, including acute interstitial nephritis, as a result of the large number of drugs to which they are exposed.(24)
Isolated cases of AKI have been reported for essentially all antiretroviral agents, but the two agents most consistently linked with acute and chronic renal effects are the nucleoside reverse transcriptase inhibitor (NRTI) tenofovir and the protease inhibitor (PI) indinavir.(6)Overall, the risk of AKI and CKD is low on tenofovir among young and relatively healthy patients (25), but this agent may induce proximal renal tubule damage that may pose increasing risk for kidney injury in patients with other risk factors. The risk of damage to the kidney from tenofovir is likely to be increased in those who already have CKD and those with prolonged exposure.(26)In one retrospective analysis of 10,000 patients exposed to tenofovir, nephrotoxicity was identified in only 2% of patients, but the risk of demonstrating a rise in serum creatinine of >0.5 mg/dL (44.2 µmol/L) was increased by an elevated baseline serum creatinine, concomitant use of another nephrotoxic agent, and older age.(27)The risk posed by indinavir, unlike tenofovir, appears to stem from chronic interstitial nephritis,(28)but this protease inhibitor is rarely used in the current era and so does not contribute substantially to current risk. (Table 2).
Clinical Features and Evaluation of Renal Disease in HIV Patients
In the post-HAART era, HIVAN should not be overlooked as a potential complication of HIV, particularly in individuals of African descent not virally suppressed on antiretroviral medication. HIVAN typically presents with a high level of proteinuria, which is often but not always nephrotic, and rapidly progressive acute kidney failure (3). HIVAN, which is not typically associated with hypertension or oedema, is generally observed in HIV-infected patients with acquired immunodeficiency syndrome (AIDS) or who otherwise have a low CD4 count and high viral loads.
However, most renal disease in HIV-infected individuals is now due to aetiologies either indirectly related to HIV infection, such as antiretroviral therapies, or to processes that may be exacerbated but not caused by HIV infection. Many of these aetiologies are generally shared with a non-HIV-infected population, but the onset may be earlier or complicated by concomitant diseases, such as HCV infection. It is helpful when reaching a diagnosis to distinguish between AKI, which represents rapid renal impairment, and CKD, which, although more slowly progressive, is generally irreversible even if further progression can be attenuated (Fig. 2).
Whether nephropathy is due to immune-related glomerulonephritis or progressive renal insufficiency due to other pathologic processes, including age-related decline in function or drug-induced renal damage, the early stages are likely to be clinically silent detectable only by laboratory testing. It is therefore appropriate to include renal function assessments within routine evaluation of HIV-infected patients, including those who are otherwise well with good infection control.(29)
Proteinuria typically provides the earliest signal of renal disease in those diseases that manifest with proteinuria (generally diseases with glomerular involvement).(30)Up to one-third of patients with HIV will demonstrate abnormal kidney function on the basis of elevated protein in the urine.(31)Although not all have a level that requires therapy, proteinuria is often associated with progressive renal disease, suggesting the need for close observation in such patients. Proteinuria, even in the microalbuminuria range (30 to 300 mg/24 hours) is an adverse prognostic sign, predicting increased health risks, including CV events. Although a 24-hour urine collection is generally considered the most accurate method for assessing proteinuria, the Infectious Diseases Society of America (IDSA) accepts a urine dipstick as a screening tool in guidelines for monitoring renal function in HIV patients. However, a protein-to-creatinine ratio on a single urine sample, commonly referred to as a spot test, provides a more accurate assessment of proteinuria with reasonable convenience.
Regardless of the degree of proteinuria, an eGFR analysis (with the use of creatinine based formulas) is warranted to evaluate renal function in all patients upon initial presentation. The accepted diagnosis of CKD is eGFR <60 ml/min/173m2 persisting for at least three months or the presence of another kidney abnormality, such as proteinuria, for more than 3 months regardless of eGFR .(32)The decision regarding how often to perform repeated eGFR assessments should be influenced by the degree of proteinuria and the presence of risk factors for CKD, the presence of diabetes or other co-morbidities, exposure to nephrotoxic drugs, smoking, dyslipidemia, or use of intravenous drugs.(29)
In young otherwise healthy individuals with good control of HIV infection and no risk factors for renal disease, routine monitoring of renal function can be reserved for periodic health assessments, but the frequency of monitoring and the types of monitoring should be intensified with increasing age and increasing number of risk factors. While dipstick urine measurements of proteinuria may be adequate in low-risk patients, concern about the potential presence of renal disease should prompt additional measures, including protein-to-creatine or albumin-to-creatine assessments and eGFR, when risk is high or the presence of proteinuria suggests a more thorough evaluation.
In HIV-infected patients, renal biopsy may be required for a definitive diagnosis of the aetiology AKI or CKD, including HIVAN. In patients with AKI, particularly those suspected of HIVAN, a kidney biopsy should be conducted promptly because of the rapid deterioration in renal function associated with this condition. One of the most common alternative causes of AKI in patients with HIV is acute interstitial nephritis (AIN), which, like HIVAN, may have characteristic features that facilitate diagnosis on biopsy. In patients with CKD, biopsy may not be necessary if the decline in renal function is consistent with a concomitant disease, such as diabetes. However, biopsy may be useful for evaluating renal involvement in patients with HCV when attempting to identify the best management strategy. In patients with multiple diagnostic possibilities, biopsy is particularly useful in guiding management.
In many cases, nephropathy cannot be reversed but the progression can be slowed substantially. The first step is to modify or eliminate potential sources of nephropathy or nephrotoxicity. This may include treating hepatitis C or switching to HAART regimens that do not include tenofovir. Early detection of declining renal function may provide an opportunity to intervene when renal damage is limited, particularly if the aetiology can be identified. With tenofovir use, for example, the immediate risk of clinically significant renal disease appears to be low in the context of slowly declining renal function, but the adverse consequences of long-term treatment may be cumulative or increased in the presence of additional risk factors for CKD.(33)
For patients with HIVAN or HIV immune complex renal disease, who have not yet started antiretroviral therapy, suppression of the viral load is the most important immediate step. Steroids may also be of benefit during the acute presentation of HIVAN. After the acute phase, progression of renal impairment may be attenuated with angiotensin converting enzyme (ACE) inhibitors.(34)Care of HIVAN (or any other kidney disease) that has advanced to ESRD or has a high likelihood of advancing to ESRD should be directed by nephrologists who can provide dialysis and who have access to sophisticated therapeutic options, such as organ transplant.
In patients with CKD, the same principles for preserving kidney function in individuals who are HIV-negative apply for those with HIV infection. This includes strict blood pressure control and glucose control (in diabetics), control of dyslipidemias, avoidance of nephrotoxic agents, and adequate doses of ACE inhibitors or other inhibitors of the renin-angiotensin system. Avoiding smoking and low levels of alcohol ingestion are also prudent. Due to the association of renal dysfunction with abnormal bone metabolism and anemia, these potential problems should be monitored.
HIV infection has been a risk factor for renal dysfunction and progression to ESRD from the earliest stages of the epidemic. Although the introduction of HAART greatly modified the risk for HIVAN, rates of renal disease are expected to climb faster in an aging HIV population even when their infection is well controlled when compared to individuals of similar age without HIV. There are numerous reasons to anticipate high rates of CKD in aging patients with HIV, including a greater number of risk factors, higher exposure to nephrotoxic drugs, and what appears to be a more rapid aging process in HIV-infected individuals. While screening for renal function should be included in routine health assessments in individuals with HIV as in individuals who are not infected with HIV, more frequent and more rigorous screening is warranted in this population.
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Chapter 1: Aging in HIV – Overview
Age-related diseases, such as atherosclerosis and osteoporosis, are being observed at a younger age in patients infected with human immunodeficiency virus (HIV) than in those without infection. The apparent acceleration in aging may be related to several causes, including persistent upregulation of the inflammatory response and the adverse effects of antiretroviral therapies. The acceleration of aging processes threaten to shorten the lifespan of patients with HIV even when immune function has been improved and the viremia remains optimally suppressed. The individual risk for specific diseases varies, but it has become important to direct attention toward opportunities to modify or circumvent the potential for irreversible damage to target organs. In general, the average age for symptomatic manifestations of processes common to aging individuals, such as bone mineral loss and neurocognitive decline, appears to be at least one decade earlier when those with HIV infection are compared to those without. In Canada, where the population of HIV-positive individuals over the age of 50 is increasing, strategies for anticipating and modifying these risks are expected to be an increasingly important part of HIV management.Show review
Chapter 2: Cardiovascular Disease
Early death from cardiovascular (CV) complications in aging individuals infected with HIV is a growing challenge in chronic HIV management. There are numerous factors that have converged to increase CV risk in individuals infected with HIV compared to age-matched individuals without infection. These include a greater prevalence of CV risk factors, the adverse effects of several antiretroviral agents that appear to contribute to CV risk, and a direct or indirect effect of HIV itself. In HIV patients with otherwise well controlled viremia, CV disease is expected to become an increasingly important cause of preventable death. The effort to modify the impact of this potential crisis depends on heightened awareness of the risks in HIV patients and aggressive monitoring and intervention for modifiable risk factors. Individualization of therapy will be increasingly important when attempting to reduce CV risks in the context of sustained HIV suppression.Show review
Chapter 4: Neurocognitive Deficit
Cognitive decline is an insidious and frequently progressive complication of human immunodeficiency virus (HIV) infection. While the introduction of highly active antiretroviral therapy (HAART) largely eliminated the dementia associated with end-stage acquired immunodeficiency syndrome (AIDS), cognitive impairment remains a common complication of HIV even in those with well controlled viremia. The incidence and the severity of HIV-associated neurocognitive disorders (HAND) are rising with an aging HIV population – a potential consequence of both increased susceptibility in older individuals and progressive impairment with longer duration of infection. The clinical challenges posed by this complication are substantial. The relative ability of specific antiretroviral therapies to cross the blood brain barrier to reduce central nervous system (CNS) viral load, and the specific, perhaps genetic, susceptibility of individual patients are among factors that may explain the variable risk of cognitive impairment. In addition, HIV-independent variables may also be important in some individuals. Clinical sensitivity to changes in cognitive function through periodic assessments is appropriate in the context of strategies to understand and prevent HAND.Show review
Chapter 5: Osteoporosis
The accelerated loss of bone density in patients with HIV infection threatens a significant health crisis in Canada and other countries with aging HIV-infected populations. There appears to be an important interaction between traditional osteoporosis risk factors and bone loss related specifically to HIV and its therapies. Consistent with accelerated aging across other organ systems, HIV-related loss of bone mineral density is a progressive condition detected soon after infection. It may persist independent of HIV suppression, and it can be exacerbated by some antiretroviral drugs. Strategies to diminish the impact of bone mineral loss depend on early screening and aggressive efforts at preventing or modifying the underlying processes. The rising rates of fracture in aging individuals with HIV infection have intensified attention on this complication, but the scope of this complication is expected to enlarge with the demographic shift that is increasing the proportion of HIV-infected individuals in the age range of vulnerability.Show review