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".)
PATHOGENESIS — The pathogenesis of HIV-associated nephropathy (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 [7]. 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 [7,8]. 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 [9]. Transgenic mouse models suggest that certain HIV genes, in particular, Nef and Vpr, are specifically involved in the pathogenesis of HIVAN [10-13].
HIV directly infects glomerular and renal tubular epithelial cells in humans with HIVAN [14,15]. 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 American ethnicity indicates that host genetic factors are also important. Human genetic studies have identified single-nucleotide polymorphisms in the APOL1 gene (on chromosome 22) that are strongly linked to increased risk of HIVAN as well as idiopathic focal segmental glomerulosclerosis (FSGS) [16-20]. However, these variants, which are present almost exclusively in individuals of West African descent, do not appear to be associated with the severity of disease among those with biopsy-proven HIVAN [21]. The mechanism through which variants in APOL1 promote HIVAN pathogenesis is not known. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'FSGS in Black patients' and "Epidemiology of chronic kidney disease".)
EPIDEMIOLOGY — HIV-associated nephropathy (HIVAN) displays a striking racial predilection for individuals of African descent and is more closely associated with African American ethnicity than any other cause of end-stage kidney disease (ESKD) except sickle cell nephropathy [22]. In studies of adult and pediatric people with HIV, 96 to 100 percent were of African descent [23-26]. According to data from the United States Renal Data System (USRDS), more than 85 percent of new ESKD cases attributed to HIVAN occur in African Americans [27].
The introduction of combination antiretroviral therapy (ART) has reduced the incidence of ESKD attributed to HIVAN [27]. In a large, urban cohort study, for example, the incidence of clinical or biopsy-proven HIVAN declined following the introduction of ART [28]. A large series of kidney biopsies from the same urban HIV population demonstrated that, between 1995 and 2004, the proportion of biopsies revealing HIVAN declined from approximately 80 percent in 1997 to less than 30 percent in 2004 [29]. Data from the USRDS demonstrate a plateau in the annual incidence of ESKD attributed to HIVAN after 1995, with evidence of further decline in subsequent years [27]. Survival of patients with ESKD attributed to HIVAN has also improved, although it remains lower than that of patients with ESKD from other causes [27].
Despite the decline in incidence of HIVAN and related ESKD among ART-treated individuals, 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 [30].
CLINICAL MANIFESTATIONS — In patients with HIV-associated nephropathy (HIVAN), the following features are usually present:
●Advanced HIV disease – 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/mm3 (64 percent had a CD4 count less than 200 cells/mm3) [25]. In two other studies, 81 and 90 percent of patients who presented with HIVAN had CD4 positive T cell counts less than 200 cells/mm3 [23,24]. It is apparent from these studies that HIVAN can present in patients with less advanced HIV infection. In addition, HIVAN has been reported in patients with acute HIV infection [4,5].
●Heavy proteinuria – In a study of 71 children with HIVAN, 72 percent had nephrotic-range proteinuria at the time of presentation [26]. Studies in adults had similar findings [23-25]. 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 [25]. 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 [31]. 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, respectively, 10 and 20 mL/min per 1.73 m2 [24,25]. 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 [26].
Other manifestations, such as hematuria, hypertension, and edema, may also be present, although the frequency 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 [24-26]:
●Hematuria – 45 to 75 percent
●Hypertension – 12 to 26 percent
●Edema – 22 to 59 percent
DIAGNOSIS — In a patient suspected of having HIV-associated nephropathy (HIVAN) based upon clinical manifestations, the diagnosis must be established by a kidney biopsy as patients suspected of having HIVAN on clinical grounds often have an alternative histologic diagnosis [32].
Histology — HIVAN is characterized by the collapsing form of focal segmental glomerulosclerosis (FSGS) (picture 1). (See "Focal segmental glomerulosclerosis: Epidemiology, classification, clinical features, and diagnosis", section on 'Collapsing variant'.)
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) [6,22]. While this unique histologic pattern was initially considered pathognomonic for HIVAN, virtually indistinguishable findings have been reported in patients treated with bisphosphonates and interferon. (See "Collapsing focal segmental glomerulosclerosis not associated with HIV infection", section on 'Bisphosphonates and other drugs'.)
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. Dedifferentiation can be demonstrated by loss of maturity markers such as synaptopodin and expression of the cell-cycle protein Ki-67 in glomerular epithelial cells from animal models and patients with HIVAN [33].
Differential diagnosis — As noted above, patients suspected of having HIVAN based upon the clinical presentation may actually have a different histologic diagnosis. As an example, in a study of 107 African American patients with HIV who had proteinuria greater than 3 g/day, kidney biopsy revealed the following [34]:
●HIVAN – 56 percent
●Classic FSGS – 21 percent
●Membranoproliferative glomerulonephritis – 6 percent
●Amyloidosis – 4 percent
●Diabetic nephropathy – 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 [29]. Overall, HIVAN accounted for only 35 percent of biopsies; other common diagnoses included non-collapsing 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 [35], and the addition of APOL1 genotype to clinical data did not significantly improve the prediction of HIVAN [36]. 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 antiretroviral therapy (ART) [30].
These and other studies illustrate the importance of obtaining a kidney biopsy to confirm a suspected diagnosis of HIVAN and exclude alternative diagnoses. The differential diagnosis in people with HIV who present with proteinuria and decreased glomerular filtration rate (GFR) includes HIVAN and also the following:
●Non-collapsing FSGS – The roles of HIV infection and ART in the pathogenesis and treatment, respectively, of non-collapsing FSGS are not known.
●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 co-infection with hepatitis C virus. (See "Overview of kidney disease in patients with HIV", section on 'Glomerulonephritis due to hepatitis C virus coinfection'.)
●Diabetic nephropathy, amyloidosis, or other noninfectious glomerulopathies – With 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 AND FOLLOW-UP
Overview of medical therapy — Treatments that have been examined for patients with HIV-associated nephropathy (HIVAN) include antiretroviral therapy (ART); inhibitors of the renin-angiotensin system, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs); and glucocorticoids. Our recommendations and suggestions pertaining to these potential therapies are as follows:
●In patients diagnosed with HIVAN who are not already receiving ART, we recommend initiation of ART, in accordance with the United States Department of Health and Human Services (HHS) Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV.
●In proteinuric and/or hypertensive patients with HIVAN, we suggest therapy with either an ACE inhibitor or ARB.
●In patients with HIVAN, we suggest not routinely treating with glucocorticoids. However, some experts use a trial of glucocorticoids in patients with progressive disease despite optimal therapy with ART and renin-angiotensin system inhibition.
The rationale for these recommendations and suggestions is presented in the following sections.
ART and HIVAN — Clinical practice guidelines recommend antiretroviral therapy (ART) initiation in all people with HIV, regardless of CD4 cell count. (See "When to initiate antiretroviral therapy in persons with HIV", section on 'Rationale for universal treatment'.)
No randomized trials have specifically examined the effect of ART in patients with HIVAN [37]. Thus, the literature suggesting benefit from ART in HIVAN consists of observational studies [35,38-40] and case reports of kidney function recovery after initiation of ART [41,42]. 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 [39]. Kidney disease outcomes were significantly better among patients treated with ART:
●Median kidney survival was significantly longer among those receiving ART (18.4 versus 3.9 months). However, the mean serum creatinine at baseline was significantly 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 (62.5 versus 81.1 percent among those with a partial virologic response).
Other retrospective biopsy series have also demonstrated improved kidney disease outcomes with ART among patients with HIVAN [35,38]. In one series, only 36 percent of patients diagnosed with HIVAN were on ART at the time of biopsy, compared with 80 percent of the overall study population [30].
Renin-angiotensin system inhibition — 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 [38,43-45]. 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 nine 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 [45]:
•During approximately six months of follow-up, the creatinine rose from 1.3 to 1.5 mg/dL among treated patients, compared with a creatinine rise from 1 to 4.9 mg/dL among untreated patients.
•During the same interval, the 24-hour protein excretion in patients given fosinopril changed from 1.6 to 1.2 g/day, compared with an increase from 0.8 to 8.5 g/day among untreated patients.
●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) [44].
The appropriate intensity of therapy with ACE inhibitors or ARBs is unknown. Both of the aforementioned studies employed a fixed, low-dose regimen of fosinopril (10 mg/day). In the absence of additional data, 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".)
Glucocorticoids — Small, uncontrolled studies have suggested that glucocorticoid therapy may improve kidney function and reduce proteinuria in patients with HIVAN [46,47], although the biologic mechanism is not clear. These studies were conducted before or early after the introduction of effective ART, and adverse events were common. Thus, in the absence of additional data, we suggest not routinely using glucocorticoid therapy for the treatment of HIVAN. It may be reasonable to consider the addition of glucocorticoids in patients with rapid progression despite optimal therapy with ART and renin-angiotensin system inhibition, weighing risks of infection and metabolic derangements against the risk of kidney disease progression.
Routine chronic kidney disease care — Care of patients with HIVAN should be shared with a nephrologist or someone with expertise in managing patients with kidney disease.
Supportive therapy of HIVAN and other CKD in patients with HIV includes appropriate medication dose adjustment, enhanced monitoring for medication toxicity, and avoidance of potentially nephrotoxic medications. (See "Overview of kidney disease in patients with HIV".)
Patients with HIVAN should have routine monitoring and care, including management of bone mineral metabolism 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".)
Prognosis — The prognosis in patients with HIVAN is poor, even among those treated with ART. Many such patients will develop 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 [25]. 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, six 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 [48]. 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.
Dialysis and transplantation — Survival rates of people with HIV on dialysis have improved substantially with the introduction of effective ART, but mortality remains higher than among dialysis patients without HIV [49]. 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. Patient and graft survival in transplant recipients with HIV appears to be similar to high-risk transplant recipients without HIV. 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".)
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
●The pathogenesis of human immunodeficiency virus (HIV)-associated nephropathy (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 HIVAN with African American ethnicity and APOL1 gene polymorphisms illustrate the importance of host genetic factors. (See 'Pathogenesis' above.)
●HIVAN is more closely associated with African American ethnicity than any other cause of end-stage kidney disease (ESKD) except sickle cell nephropathy. The introduction of antiretroviral therapy (ART) has reduced the incidence of ESKD attributed to HIVAN. (See 'Epidemiology' above.)
●In patients with HIVAN, the following features are common (see 'Clinical manifestations' above):
•African American ethnicity
•Advanced HIV disease
•Heavy proteinuria
•Rapid decline in kidney function
●In a patient suspected of having HIVAN based upon clinical manifestations, the diagnosis should be established by a kidney biopsy as many patients suspected of having HIVAN on clinical grounds will have an alternative histologic diagnosis that may alter management. (See 'Diagnosis' above and 'Differential diagnosis' above.)
●HIVAN is characterized by the collapsing form of focal segmental glomerulosclerosis (FSGS) (picture 1). 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). (See 'Histology' above.)
●In patients diagnosed with HIVAN who are not already receiving ART, we recommend initiation of ART (Grade 1B). Our stance is in agreement with the United States Department of Health and Human Services (HHS) Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV, which recommend the initiation of ART in all people with HIV. (See 'Overview of medical therapy' above and 'ART and HIVAN' above.)
●In proteinuric and/or hypertensive patients with HIVAN, we suggest therapy with either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) (Grade 2C). (See 'Overview of medical therapy' above and 'Renin-angiotensin system inhibition' above.)
●In patients with HIVAN, we suggest not routinely treating with glucocorticoids (Grade 2C). (See 'Overview of medical therapy' above and 'Glucocorticoids' above.)
●The prognosis in patients with HIVAN is poor, even among those treated with ART. Many such patients will develop ESKD. (See 'Prognosis' above.)
●Survival rates of people with HIV on dialysis are now similar to rates among patients on dialysis without HIV. Transplantation is a viable option for patients with HIVAN and ESKD, although there is a risk of HIVAN recurrence in the allograft. Patient and graft survival may be similar to high-risk transplant recipients without HIV. (See 'Dialysis and transplantation' above.)
