HIV-associated nephropathy (HIVAN)

INTRODUCTION — Human immunodeficiency virus (HIV) infection has been associated with both acute kidney injury (AKI) and chronic kidney disease (CKD). (See "Overview of kidney disease in patients with HIV".)

HIV-associated nephropathy (HIVAN), the classic kidney disease associated with HIV infection, was first described in 1984 as a complication of AIDS [1-3] although HIVAN may also occur in patients with less advanced HIV infection or following acute seroconversion [4,5]. Histologically, HIVAN is a collapsing form of focal segmental glomerulosclerosis (FSGS) (picture 1) accompanied by microcystic tubular dilatation and interstitial inflammation [6].

Issues related to HIVAN will be discussed in this topic. An overview of kidney disease in people with HIV and discussions of electrolyte abnormalities, dialysis, and transplantation in people with HIV are provided elsewhere:

●(See "Overview of kidney disease in patients with HIV".)

●(See "Electrolyte disturbances with HIV infection".)

●(See "Human immunodeficiency virus and dialysis".)

●(See "Kidney transplantation in adults: Kidney transplantation in patients with HIV".)

EPIDEMIOLOGY — HIVAN displays a striking racial predilection for individuals of African descent [7]. In studies of adult and pediatric people with HIV, 96 to 100 percent were of African descent [8-11]. According to data from the United States Renal Data System (USRDS), more than 85 percent of new end-stage kidney disease (ESKD) cases attributed to HIVAN occur in African Americans [12]. In individuals of African descent, the presence of APOL1 risk variants have been associated with a higher incidence of HIVAN [13]. (See 'Pathogenesis' below.)

The introduction of combination antiretroviral therapy (ART) substantially reduced the incidence of ESKD attributed to HIVAN [12]. In a large, urban cohort study, for example, the incidence of suspected or biopsy-proven HIVAN declined following the introduction of ART [14]. A large series of kidney biopsies in people with HIV between 1995 and 2004 demonstrated a decline in the proportion of biopsies revealing HIVAN from approximately 80 percent in 1997 to less than 30 percent in 2004 [15]. Data from the USRDS demonstrate a plateau in the annual incidence of ESKD attributed to HIVAN after 1995 [12]. Survival of patients with ESKD attributed to HIVAN has also improved although it remains lower than that of patients with ESKD from other causes [12].

Despite the decline in incidence of HIVAN and related ESKD among individuals treated with ART, HIVAN remains an important cause of kidney disease in people with HIV who are not taking ART due to nonadherence, intolerance, or previously undiagnosed HIV [16].

PATHOGENESIS — The pathogenesis of HIVAN is hypothesized to involve several factors:

●Infection of kidney epithelial cells by HIV and expression of HIV genes within infected kidney cells

●Host factors, including genetic susceptibility

Much of our current understanding of the pathogenesis of HIVAN has been derived from animal models, in particular the Tg26 HIV-1 transgenic mouse model [17]. This transgenic mouse model expresses a gag/pol-deleted HIV-1 provirus in the kidney and develops proteinuria, kidney failure, and histologic findings resembling human HIVAN [17,18]. Following the reciprocal transplantation of kidneys between transgenic and wild-type mice, kidney disease develops only in kidneys donated by transgenic animals, suggesting that HIV gene expression in kidney cells is required for the development of HIVAN [19]. Transgenic mouse models suggest that certain HIV genes, in particular Nef and Vpr, are specifically involved in the pathogenesis of HIVAN [20-23].

HIV directly infects glomerular and kidney tubular epithelial cells in humans with HIVAN [24,25]. In addition, in vitro experiments have shown that HIV transgene expression induces dedifferentiation and proliferation of glomerular epithelial cells and impairs cytokinesis in tubular epithelial cells.

The strong association between HIVAN and African ancestry indicates that host genetic factors are also important. Human genetic studies have identified single-nucleotide polymorphisms in the APOL1 gene that are strongly linked to increased risk of HIVAN and non-HIVAN focal segmental glomerulosclerosis (FSGS) [13,26-29]. However, these variants, which are present almost exclusively in individuals of African descent but have been less commonly identified in other populations, are not required for the development of HIVAN and do not appear to be associated with the severity of disease among those with biopsy-proven HIVAN [30]. The mechanisms through which variants in APOL1 promote HIVAN and other forms of FSGS have not been fully elucidated, although growing evidence suggests a gain-of-function effect of the risk variants. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'FSGS in Black patients' and "Epidemiology of chronic kidney disease".)

PATHOLOGY — HIVAN is characterized by the collapsing form of focal segmental glomerulosclerosis (FSGS) (picture 1). (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis", section on 'Histologic variants'.)

In addition to collapsing FSGS, HIVAN is typically characterized by dilated tubules and significant interstitial inflammation. Tubuloreticular inclusions may also be identified on electron microscopy (picture 2) [6,7]. While this unique histologic pattern was initially considered pathognomonic for HIVAN, virtually indistinguishable findings have been reported in patients with systemic lupus erythematosus, patients treated with bisphosphonates and interferon, and patients with other viral infections, including SARS-CoV-2 infection. (See "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)", section on 'Bisphosphonates and other drugs' and "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)", section on 'Infections' and "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension".)

The glomerular lesion of HIVAN is also characterized by dedifferentiation and proliferation of glomerular epithelial cells, which are typically considered terminally differentiated cells, resulting in pseudocrescent formation [31].

CLINICAL MANIFESTATIONS — In patients with classic HIVAN, the following features are usually present:

●Advanced HIV disease – Patients with HIVAN typically have a CD4 count less than 200 cells/microL. In a study of 57 patients with proven HIVAN, approximately one-half of whom were taking antiretroviral therapy (ART), the mean HIV viral load was greater than 30,000 copies/mL, and the mean CD4 cell count was 127 cells/microL (64 percent had a CD4 count less than 200 cells/microL) [10]. In two other studies, 81 and 90 percent of patients who presented with HIVAN had CD4 positive T cell counts less than 200 cells/microL [8,9]. In addition, HIVAN has been reported in patients with acute HIV infection [4,5].

●Nephrotic-range proteinuria – In a study of 71 children with HIVAN, 72 percent had nephrotic-range proteinuria at the time of presentation [11]. Studies in adults had similar findings [8-10]. Among 57 patients with HIVAN, for example, mean proteinuria was 4.1 g/day, and only 14 percent of patients had proteinuria less than 1.5 g/day [10]. However, patients with HIVAN may have substantially less proteinuria early during the course of their disease. As an example, a study from South Africa found early HIVAN in six of seven ART-naïve patients who had persistent moderately increased albuminuria (formerly called "microalbuminuria"); such patients would rarely undergo kidney biopsy in routine clinical practice [32]. These findings suggest that HIVAN should also be considered in patients with lesser degrees of proteinuria.

●Rapid decline in kidney function – At the time of HIVAN diagnosis, adult patients often have severely reduced kidney function, which is attributed to the rapidly progressive course. In two studies of adults with HIVAN, the mean estimated glomerular filtration rates (eGFR) at the time of HIVAN diagnosis were 10 and 20 mL/min per 1.73 m² [9,10]. Children may not have similarly severe kidney dysfunction at the time of presentation, although this may be a result of ascertainment bias rather than a true difference in the disease course. Among 71 South African children diagnosed with HIVAN, for example, only one-third had an eGFR less than 60 mL/min per 1.73 m² [11].

Other manifestations, such as hematuria, hypertension, and edema, may also be present although the frequencies of hypertension and edema are lower than may be expected in patients with severe proteinuria and decreased eGFR. In three studies of adult and pediatric patients with HIVAN, the following characteristics were observed [9-11]:

●Hematuria – 45 to 75 percent

●Hypertension – 12 to 26 percent

●Edema – 22 to 59 percent

In addition, the presence of enlarged, hyperechogenic kidneys on ultrasonography has been reported in more than 50 percent of patients with HIVAN [33].

DIAGNOSIS

When to suspect HIVAN — The diagnosis of HIVAN should be suspected in any patient with HIV who presents with nephrotic-range proteinuria and rapidly declining kidney function, even in the absence of edema. Our suspicion is particularly high if the patient has a CD4 cell count <200 cells/microL, HIV viremia, and/or has a history of nonadherence to antiretroviral therapy (ART). HIVAN should also be considered in patients with milder proteinuria; however, other causes (eg, medication toxicity) may be more likely. (See 'Clinical manifestations' above.)

Establishing the diagnosis — Kidney biopsy is currently the only way to establish a definitive diagnosis of HIVAN as patients suspected of having HIVAN on clinical grounds often have an alternative histologic diagnosis [34]. There are no specific laboratory findings that can be used to distinguish HIVAN from other forms of glomerular disease, including other forms of HIV-associated kidney disease. If a kidney biopsy cannot be performed safely, we manage patients with suspected HIVAN similarly as those with biopsy-proven HIVAN. (See 'Pathology' above and 'Initial therapy' below.)

As noted above, patients suspected of having HIVAN based on the clinical presentation may actually have a different histologic diagnosis. As an example, in a study of 107 African American people with HIV who had proteinuria greater than 3 g/day, kidney biopsy revealed the following [35]:

●HIVAN – 56 percent

●Classic focal segmental glomerulosclerosis (FSGS) – 21 percent

●Membranoproliferative glomerulonephritis – 6 percent

●Amyloidosis – 4 percent

●Diabetic kidney disease – 4 percent

●Lupus-like immune complex glomerulonephritis – 4 percent

●Other – 5 percent

In a series of 152 kidney biopsies performed in adults with HIV at the same urban center between 1995 and 2004, the proportion of kidney biopsies demonstrating HIVAN declined over time [15]. Overall, HIVAN accounted for only 35 percent of biopsies; other common diagnoses included noncollapsing FSGS (22 percent of biopsies) and a variety of immune complex glomerular diseases. In an updated biopsy series from the same center, both HIVAN and immune complex kidney diseases occurred predominantly in African Americans with advanced HIV disease [36], and the addition of APOL1 genotype to clinical data did not significantly improve the prediction of HIVAN [37]. In a more contemporary series of 437 kidney biopsies interpreted at a single center between 2010 and 2018, HIVAN remained the third most common biopsy diagnosis in people with HIV and the most common finding among those not taking ART [16].

These and other studies illustrate the importance of obtaining a kidney biopsy to confirm a suspected diagnosis of HIVAN and exclude alternative diagnoses. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis in people with HIV who present with proteinuria and decreased glomerular filtration rate (GFR) includes HIVAN and also the following:

●Noncollapsing focal segmental glomerulosclerosis (FSGS) – In the modern era of antiretroviral therapy (ART), there has been a shift away from the classic presentation of HIVAN to a more indolent presentation of slowly progressive kidney disease. Histologically, this is characterized as noncollapsing FSGS and is more often observed in people with HIV receiving ART, who generally have CD4 cell counts >200 cells/microL and who have undetectable viral loads. To distinguish this form of noncollapsing FSGS from classic HIVAN, the Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference classified this entity as FSGS (not otherwise specified) in the setting of HIV [38].

The roles of HIV infection and ART in the pathogenesis and treatment, respectively, of noncollapsing FSGS are not known. Case series of kidney biopsies performed after widespread use of ART demonstrate a decrease in the prevalence of HIVAN and a simultaneous increase in the prevalence of noncollapsing FSGS. These data suggest that noncollapsing FSGS is a milder form of HIVAN that is partially treated with ART although this has not been proven [9,15].

●Immune complex-mediated glomerulonephritis, including immunoglobulin A (IgA) nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, and a "lupus-like" proliferative glomerulonephritis. (See "Overview of kidney disease in patients with HIV", section on 'Immune complex kidney disease'.)

●Glomerulonephritis due to coinfection with hepatitis C or hepatitis B virus. (See "Overview of kidney disease in patients with HIV", section on 'Glomerulonephritis due to hepatitis C virus coinfection' and "Kidney disease associated with hepatitis B virus infection".)

●Diabetic kidney disease, amyloidosis, or other noninfectious glomerulopathies – With the aging of the patient population with HIV, comorbid kidney disease due to traditional chronic kidney disease (CKD) risk factors is increasingly important. (See "Overview of kidney disease in patients with HIV".)

TREATMENT — Treatments that have been examined for patients with HIVAN include antiretroviral therapy (ART); renin-angiotensin system inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs); and glucocorticoids. None of these therapies have been evaluated in randomized clinical trials. Our approach to the treatment of HIVAN is presented below.

Initial therapy

Antiretroviral therapy for all patients — All patients with HIV infection should receive ART, regardless of CD4 count. (See "When to initiate antiretroviral therapy in persons with HIV", section on 'Universal treatment'.)

●For patients with HIVAN who are not already receiving ART, ART should be initiated as soon as possible. The selection of ART regimen, particularly in the setting of impaired kidney function, is discussed in detail elsewhere. (See "Selecting antiretroviral regimens for treatment-naive persons with HIV-1: Patients with comorbid conditions", section on 'Reduced kidney function'.)

●For patients with HIVAN who are already receiving ART, medication adherence should be assessed. Those who are adherent to ART but have a detectable viral load should be evaluated for drug resistance mutations to determine if their ART regimen should be changed. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

In all patients, the ART regimen may need to be adjusted for estimated glomerular filtration rate (eGFR). (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)

No randomized trials have specifically examined the effect of ART in patients with HIVAN [39]. Evidence suggesting benefit from ART in HIVAN comes primarily from observational studies [36,40-42] and case reports of kidney function recovery after initiation of ART [43,44]. In addition, data from the United States Renal Data System (USRDS) suggest a benefit of ART on the epidemiology of end-stage kidney disease (ESKD) attributed to HIVAN.

As an example, the association of ART initiation with kidney disease outcomes was analyzed in a retrospective cohort of 36 patients with biopsy-proven HIVAN who did not require dialysis at the time of kidney biopsy; 26 were treated with ART, and 10 received no ART [41]. Kidney disease outcomes were significantly better among patients treated with ART:

●Median kidney survival was substantially longer among those receiving ART (18.4 versus 3.9 months). However, the mean serum creatinine at baseline was lower in patients who received ART (4.7 versus 7.8 mg/dL), and the results were not adjusted for baseline kidney function.

●Among patients treated with ART within three months of biopsy, the risk of needing dialysis was lower if a complete virologic response was achieved although this was not significant.

Other retrospective biopsy series have also demonstrated improved kidney disease outcomes with ART among patients with HIVAN [36,40].

Additional therapies for proteinuria or hypertension

ACE inhibitors or ARBs — Patients with HIVAN who have proteinuria and/or hypertension should be treated with an ACE inhibitor or ARB. This approach is similar to that for patients with proteinuric chronic kidney disease (CKD), as discussed elsewhere. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of renin-angiotensin system inhibitors on progression of CKD' and "Overview of hypertension in acute and chronic kidney disease", section on 'Choice of antihypertensive therapy'.)

The efficacy and safety of ACE inhibitors and ARBs have been extrapolated from rigorous studies in other glomerular diseases and from observational studies in patients with HIVAN [40,45-47]. There are no randomized trials of renin-angiotensin system inhibitors for the treatment of HIVAN.

The following examples illustrate the range of findings in support of treating patients who have HIVAN with ACE inhibitors or ARBs:

●A short-term study of 11 non-nephrotic and 9 nephrotic patients with biopsy-proven HIVAN reported more favorable changes in serum creatinine and 24-hour urine protein excretion among patients treated with fosinopril (10 mg/day) as compared with untreated patients [47].

●A subsequent study demonstrated significantly longer kidney survival for patients treated with fosinopril as compared with untreated patients, despite similar characteristics and kidney function at baseline (median kidney survival of 480 days for treated patients versus 146 days for untreated patients) [46].

In the absence of data to guide dosing, it is reasonable to adopt the goals for blood pressure and proteinuria control used in other nondiabetic chronic kidney diseases (CKD). (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

SGLT2 inhibitors — As with other patients with proteinuric CKD, patients with HIVAN who have persistent proteinuria in spite of treatment with an ACE inhibitor or ARB may benefit from addition of a sodium-glucose cotransporter 2 (SGLT2) inhibitor. (See "Overview of the management of chronic kidney disease in adults", section on 'Patients with proteinuria'.)

There are currently no data on the efficacy and safety of SGLT2 inhibitors for the treatment of HIVAN. However, data from large randomized trials have demonstrated that SGLT2 inhibitors slow progression of nondiabetic proteinuric CKD, including focal segmental glomerulosclerosis (FSGS) [48,49]. These studies are presented in detail elsewhere. (See "Overview of the management of chronic kidney disease in adults", section on 'Patients with proteinuria'.)

No role for routine glucocorticoids — There is generally no role for routine glucocorticoids in patients with HIVAN. Although small observational studies have suggested that glucocorticoid therapy may improve kidney function and reduce proteinuria in patients with HIVAN [50,51], these studies were conducted before or early after the introduction of effective ART, and adverse events were common. In patients whose kidney function is not improving with therapy, the use of glucocorticoids may be considered on a case-by-case basis, weighing the risks of infection and metabolic derangements against the risk of kidney disease progression.

Monitoring response to therapy — All patients with HIVAN should be monitored during therapy to evaluate treatment response. We assess the serum creatinine level, eGFR, and urine protein excretion (by spot urine protein-to-creatinine ratio or spot urine albumin-to-creatinine ratio), with the frequency of assessments guided by the severity of the clinical presentation. In addition, we routinely monitor the patient's HIV viral RNA level and CD4 cell count. (See "Patient monitoring during HIV antiretroviral therapy".)

Patients with HIVAN should have routine monitoring and care, including management of complications of CKD and timely preparation for dialysis or transplantation, similar to patients with CKD who do not have HIV. The general care of such patients is discussed elsewhere. (See "Overview of the management of chronic kidney disease in adults".)

Dialysis and transplantation — Despite treatment with ART and adjunctive therapies such as renin-angiotensin inhibitors and SGLT2 inhibitors, some patients with HIVAN will progress to ESKD and require kidney replacement therapy with dialysis and/or kidney transplantation. (See 'Prognosis' below.)

Survival rates of people with HIV on dialysis have improved substantially with the introduction of effective ART, but mortality remains higher than among patients on dialysis without HIV [52]. There is no evidence favoring one dialysis modality over another. Specific issues related to HIV infection in patients on dialysis are discussed separately. (See "Human immunodeficiency virus and dialysis".)

Transplantation is a viable option for patients with HIVAN and ESKD; however, there is a risk of HIVAN recurrence in the allograft. Kidney transplantation in people with HIV, including the use of HIV-positive donor organs, is presented elsewhere. (See "Kidney transplantation in adults: Kidney transplantation in patients with HIV".)

PROGNOSIS — The prognosis in patients with HIVAN is poor, even among those treated with antiretroviral therapy (ART). Many such patients will develop end-stage kidney disease (ESKD). The following examples illustrate the range of findings:

●A French study examined the outcomes of 57 patients diagnosed with HIVAN, one-half of whom were already taking ART at the time of diagnosis [10]. The other one-half initiated ART within one month of the diagnosis of HIVAN. Most patients were also treated with inhibitors of the renin-angiotensin system. A total of 51 patients were followed for a median of approximately two years. During that time, 6 patients died and 30 developed ESKD (71 percent of those followed had one of these two outcomes). Patients who were already taking ART at the time of HIVAN diagnosis were more likely to develop ESKD, as were those who developed HIVAN despite complete virologic suppression.

●A British study followed 31 patients with biopsy-proven HIVAN for a median of four and a half years; ART was initiated in 29 of the 31 patients within one month of HIVAN diagnosis [53]. ESKD developed in 15 of these 31 patients (48 percent). Virologic suppression was achieved in approximately 70 percent of patients, with no difference among patients who did and did not subsequently develop ESKD.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Overview – HIV-associated nephropathy (HIVAN), the classic kidney disease associated with HIV infection, is a collapsing form of focal segmental glomerulosclerosis (FSGS) accompanied by microcystic tubular dilatation and interstitial inflammation. (See 'Introduction' above and 'Pathology' above.)

●Pathogenesis – The pathogenesis of HIVAN is hypothesized to involve direct infection of kidney epithelial cells by HIV with subsequent expression of HIV genes in a genetically susceptible host. The strong associations of HIV with African ancestry and APOL1 gene polymorphisms illustrate the importance of host genetic factors. (See 'Pathogenesis' above.)

●Clinical manifestations – HIVAN classically presents with heavy proteinuria and a rapid decline in kidney function in a person with advanced HIV disease. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of HIVAN should be suspected in any patient with HIV who presents with nephrotic-range proteinuria and rapidly declining kidney function. Our suspicion is particularly high if the patient has a CD4 cell count <200 cells/microL, HIV viremia, and/or has a history of nonadherence to antiretroviral therapy (ART). Kidney biopsy is currently the only way to establish a definitive diagnosis of HIVAN. (See 'Diagnosis' above.)

●Treatment – Our approach to the treatment of HIVAN is as follows:

•All patients with HIV infection should receive ART, regardless of CD4 count. For patients with HIVAN who are not already receiving ART, ART should be initiated as soon as possible. For patients who are already receiving ART, medication adherence should be assessed. (See 'Antiretroviral therapy for all patients' above.)

•Patients with HIVAN who have proteinuria and/or hypertension should be treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blockers (ARB). This approach is similar to that for patients with proteinuric chronic kidney disease (CKD). Patients who have persistent proteinuria in spite of treatment with an ACE inhibitor or ARB may benefit from addition of a sodium-glucose cotransporter 2 (SGLT2) inhibitor. (See 'ACE inhibitors or ARBs' above and 'SGLT2 inhibitors' above.)

•There is generally no role for routine glucocorticoids in patients with HIVAN. In patients whose kidney function is not improving with therapy, the use of glucocorticoids may be considered on a case-by-case basis, weighing the risks of infection and metabolic derangements against the risk of kidney disease progression. (See 'No role for routine glucocorticoids' above.)

●Prognosis – The prognosis in patients with HIVAN is poor, even among those treated with ART. Many such patients will develop end-stage kidney disease (ESKD). (See 'Prognosis' above.)