HIV-Associated Nephropathy and Other HIV-Related Renal Disorders

Updated: Mar 16, 2023
  • Author: Moro O Salifu, MD, MPH, MBA, MACP; Chief Editor: Vecihi Batuman, MD, FASN  more...
  • Print

Practice Essentials

HIV-positive individuals are at increased risk for a variety of renal disorders, including acute kidney injury (AKI), HIV-associated nephropathy (HIVAN), comorbid chronic kidney disease (CKD), thrombotic microangiopathy, and treatment-related kidney toxicity. [1, 2] HIVAN, the classic kidney disease of HIV infection, has become less common with widespread use of antiretroviral therapy (ART); simultaneously, however, the prevalence of other kidney diseases has increased. [3]

Combined ART can prevent and reverse HIVAN. However, focal segmental glomerulosclerosis, arterionephrosclerosis, and diabetic nephropathy are increasingly common in individuals who have received such therapy for many years. [4] Guidelines recommending earlier initiation of ART may further reduce the incidence of HIVAN, but the overall risk-benefit for kidney health is unclear. 

The distribution of HIV-associated kidney diseases continues to vary across geographic regions worldwide. The reasons for this diversity are complex and include a critical role of APOL1 variants and possibly other genetic factors, disparities in access to effective antiviral therapies, and other risk factors not fully understood. [4]

The spectrum of renal pathology in HIV-positive individuals includes lesions directly related to intrarenal HIV gene expression and lesions related to comorbidities, drug effects, immune dysregulation, and co-infections. [4] HIV-related kidney diseases fall under four pathologic classifications [5] :

  • Glomerular-dominant nephropathies: HIVAN and immune complex–mediated glomerular diseases 
  • Tubulointerstitial-dominant nephropathies: HIVAN-related tubulointerstitial injury; ART-induced acute tubular injury; drug-induced (other than ART) tubulointerstitial nephritis; direct renal parenchymal infection by viral, bacterial or fungal pathogens
  • Vascular-dominant nephropathies: thrombotic microangiopathy (reported in the early years of the AIDS epidemic, but now rarely reported) and atherosclerosis
  • Other nephropathies in the setting of HIV infection: diabetic nephropathy and age-related nephrosclerosis

HIVAN occurs in advanced HIV disease and is classically associated with rapid progression to end-stage renal disease (ESRD). HIVAN almost exclusively affects persons of African descent, who account for approximately 90% of HIVAN-related cases of ESRD. [1]

HIVAN has a distinct histology, representing a collapsing form of focal segmental glomerulosclerosis (FSGS). The pathogenesis of HIVAN requires local HIV infection of the kidney, with the virus infecting tubular and glomerular epithelial cells. Although FSGS is the predominant glomerular lesion in HIVAN, other reported glomerular lesions in patients with HIV include IgA nephropathy, cryoglobulinemia, amyloidosis, and a lupuslike immune complex glomerulopathy. [6]

In addition, as patients with HIV infection age, comorbid kidney diseases such as diabetic nephropathy and arterionephrosclerosis have become increasingly common. When secondary FSGS develops in these patients, the potential overlap with HIVAN can be diagnostically challenging. Kidney biopsy is required to distinguish between these lesions. [5]

For other discussions on management of HIV infection, see HIV Disease, Pediatric HIV Infection, and Antiretroviral Therapy for HIV Infection.

For patient education information, see HIV/AIDS.



The cellular target in the development of HIVAN is probably the renal glomerular and tubular epithelium. Using in situ hybridization and polymerase chain reaction assays to detect HIV-1 DNA and messenger ribonucleic acid (mRNA), investigators have shown that renal glomerular and tubular epithelial cells are infected by HIV-1 in patients with HIVAN; this argues strongly for localized replication of HIV-1 in the kidney and for the existence of a renal viral reservoir.

Further, circularized viral DNA, a marker of recent nuclear import of full-length, reverse-transcribed RNA, has been detected in kidney biopsy samples from patients with HIVAN, suggesting active replication in renal tissue. [7] However, the mechanisms of virus-induced renal injury remain undetermined.

Peculiar histopathologic features of HIVAN are the enhanced proliferation and the loss of differentiation markers of glomerular epithelial cells. In one study, HIV-1 infection was shown to kill renal tubular epithelial cells in vitro by triggering an apoptotic pathway involving caspase activation and Fas up-regulation, suggesting that apoptosis of nonlymphoid cells can be directly induced by HIV-1. The net and long-standing glomerular and tubular epithelial cell damage leads to proteinuria, glomerulosclerosis, and tubulointerstitial scarring.

The role of cytokines has not been established, and although their presence is not essential for the development of HIVAN, cytokines may modify the progression of infection or a patient's susceptibility to infection. The levels of cytokines are increased in renal biopsy samples from patients with HIVAN.

In one study, mesangial and tubular cell production of interleukin-6 and tumor necrosis factor–alpha was shown to be a potent stimulus for HIV-1 expression in HIV-1–infected monocytes. [8] Viral replication in response to cytokines may play an important role in the pathogenesis of HIVAN.


In 120 patients with HIVAN and chronic kidney disease (CKD) and 108 controls from a South African Black population, Kasembeli et al found that 79% of patients with HIVAN and 2% of the controls carried two risk alleles: APOL1 G1 and G2 variants. In this study, any individual possessing any combination of two APOL1 risk alleles had 89-fold increased odds (95% CI: 18 - 912; P < 0.001) of developing HIVAN compared with HIV-positive controls. [9]  In contrast, HIV-positive Ethiopians, who lack APOL1 risk variants, do not develop HIVAN. [5]  

Coding variants in APOL1 are present only on African-ancestry haplotypes. They are thought to protect against African trypanosomiasis (African sleeping sickness), a deadly parasitic disease caused by two strains of Trypanosoma brucei, one of which is found in East Africa, while the other affects West Africa. APOL1 encodes apolipoprotein L1, which confers innate immunity against most strains of T brucei; G2 variants extend immunity to T.b. rhodesiense and G1 associates with asymptomatic carriage of T.b. gambiense, the causes of acute and chronic African human trypanosomiasis, respectively. [10]  

As a consequence of the West African diaspora in the Americas and more recent African emigrations, APOL1 variants are widely dispersed globally (eg, 21% and 13% for G1 and G2, respectively, in African Americans). [5]



Acute kidney injury (AKI) is more common in HIV-infected persons than in the general population. Although HIV-asociated AKI has become less common since the introduction of potent antiretroviral therapy, the incidence remains substantial, and the trend is toward more severe AKI and increased mortality risk. [1]  

The prevalence of HIV-associated chronic kidney disease (CKD) varies geographically and depends on the definition of CKD used. In North America and Europe, HIV-associated CKD prevalence ranges from 4.7%–9.7% when CKD is defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. The prevalence of CKD in the United States increases to 15.5% with a change in definition to include a reduced eGFR and/or proteinuria. [11]  

Screening studies defining persistent proteinuria as an indicator of CKD revealed prevalence rates of 27% in India, 12.3% in Iran, and 5.6% in Brazil. Africa has the highest prevalence of CKD in people living with HIV infection [2] ; in Africa, however, the prevalence of HIV-associated renal disease is widely variable: 38% in Nigeria, 33.5% in, 26% in Cote d’Ivoire, 20% in Uganda, 11.5% in Kenya, and 5.5%–6% in South Africa. [11]  

HIV-positive individuals now comprise 1.5% of the United States end-stage renal disease (ESRD) population, and the prevalence of ESRD in this population continues to rise. [12]  There is a twofold to 20-fold greater risk of ESRD compared with the general population, with incidence rates in the US and Europe of 3 to 10 per 1,000 person-years in HIV-positive individuals versus 0.5 per 1,000 person-years in HIV-negative individuals. [11]  There is also a significant racial disparity in the burden of ESRD, with a six times higher risk borne by individuals of African origin. [12]



Kidney transplantation in HIV-positive recipients is associated with excellent 1-year and 3-year recipient and allograft survival rates, intermediate to those observed in the overall US kidney transplant population and in a higher-risk subgroup of recipients ≥65 years of age. Registry data also suggest good 5- and 10-year outcomes, with an improvement in survival compared with patients who remain on the waiting list. [13]


Clinical Presentation and Workup

Patients with HIV-associated nephropathy (HIVAN) typically present with a nephrotic syndrome consisting of nephrotic-range proteinuria (> 3.5 g/d), azotemia, hypoalbuminemia, and hyperlipidemia. Edema is uncommon in HIVAN, yet many authors describe it as a characteristic of HIVAN. The salt-losing propensity and high oncotic pressure contributed by marked hypergammaglobulinemia in these patients have been suggested as possible explanations for this puzzling observation.

CD4+ T-cell count

The CD4+ T-cell count in patients with HIVAN is usually depressed below 200 cells/µL, but HIVAN has been reported in patients with higher CD4 counts. The prognosis for renal survival is worse in patients with AIDS, especially if their CD4 count is less than 50 cells/µL. [14]

Ultrasound and CT scan

Patients with HIVAN are not typically hypertensive, even in the face of kidney insufficiency, and their kidneys are usually normal to large in size and highly echogenic on ultrasonograms, as well as on CT scans. This may result from prominent interstitial expansion by cellular infiltrate and markedly dilated tubules containing voluminous casts.


Routine urinalysis may occasionally reveal findings of nonnephrotic proteinuria in patients being evaluated for other medical conditions. The urinalysis reveals microhematuria, leukocytes, hyaline casts, and oval fat bodies, but no cellular casts. Serum complement levels are normal.


Electrolyte abnormalities, such as hyponatremia and hyperkalemia, may be observed in patients with HIVAN and may reflect an increase in total body water (from nephrotic syndrome or syndrome of inappropriate secretion of antidiuretic hormone [SIADH]) or from hyporeninemic hypoaldosteronism, respectively.

SIADH may result from concomitant pulmonary infection or from persistent nausea from medications or gastrointestinal disease. Hyporeninemic hypoaldosteronism, a cause of type IV renal tubular acidosis manifesting as hyperkalemia with normal anion gap metabolic acidosis, is much more common when kidney insufficiency is present.


Kidney Biopsy

The decision to obtain a biopsy sample is somewhat controversial in the general medical community. Even if a patient presents with the classic clinical features of HIV-associated neuropathy (HIVAN), clinical consideration is predictive of the biopsy diagnosis in only 55-60% of patients.

Therefore, to distinguish HIVAN from other forms of renal disease (eg, immune complex glomerulonephritis, immunoglobulin-A nephropathy), patients who are seropositive for HIV require a kidney biopsy. The typical practice is to obtain a biopsy specimen if the patient's daily protein excretion is greater than 1 g.


Findings from light microscopy of kidney biopsy tissue are diagnostic in most cases. The most common histologic light microscopy finding is a collapsing form of focal segmental glomerulosclerosis. [15] The glomerular capillary tuft is collapsed (see the first image below) and may be segmentally or globally sclerosed. Visceral epithelial cells are hypertrophied and form a characteristic pseudocrescent in the Bowman space. Tubulointerstitial scarring, atrophy, and marked dilatation of the tubules (microcystic dilatations) are usually present (see the second image below).

Light microscopy with trichrome staining showing t Light microscopy with trichrome staining showing the collapse of the glomerular tuft, with segmental glomerular and interstitial sclerosis (bluish staining). The renal tubules are dilated and filled with proteinaceous material.
Light microscopy showing prominent microcystic dil Light microscopy showing prominent microcystic dilatation of renal tubules filled with proteinaceous material; this finding is characteristic of human immunodeficiency virus (HIV)–associated nephropathy, although it may also be observed in chronic glomerulonephritis.

Immunofluorescent microscopy helps to identify positive staining for albumin and immunoglobulin G in epithelial cells and for immunoglobulin M, C3, and, occasionally, A in mesangial or sclerotic areas.

Electron microscopy reveals wrinkling of the basement membranes, epithelial cell proliferation, and focal foot process effacement. Tubuloreticular structures in the glomerular endothelial cells (consisting of ribonucleoprotein and membrane, the synthesis of which is stimulated by alpha interferon) is highly predictive of HIVAN (see the image below).

Electron microscopy showing a segment of the glome Electron microscopy showing a segment of the glomerular basement membrane; foot process effacement (black arrow) and prominent tubuloreticular inclusions (red arrow) are present.

Antiretroviral Drugs and Kidney Function

Most HIV medications are well tolerated, even in the presence of kidney insufficiency. [16]  The (potential) toxicity of the nucleoside reverse transcriptase inhibitors (NRTIs—ie, zidovudine, [17] didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine) uniformly manifests as type B lactic acidosis. However, didanosine may cause electrolyte abnormalities, such as hypokalemia, hyponatremia, hypermagnesemia, and hyperuricemia, and stavudine may cause hyperuricemia.

Tenofovir disoproxil fumarate (tenofovir DF) is an NRTI with the potential for cumulative kidney toxicity. Dose adjustment is indicated when creatinine clearance is less than 50 mL/min. Tenofovir alafenamide (tenofovir AF), a prodrug, is a novel nucleotide reverse transcriptase inhibitor that has efficacy similar to that of tenofovir DF but an improved safety profile. [18]

Except for nevirapine, which may cause lactic acidosis, the non-nucleoside reverse transcriptase inhibitors (NNRTIs—ie, nevirapine, delavirdine, efavirenz, etravirine) have no reported significant kidney toxicity.

Dose adjustment should be made in patients receiving NRTIs when the glomerular filtration rate (GFR) falls below 50 mL/min. Patients receiving NNRTIs may also receive a dose adjustment when the GFR falls below 50 mL/min. No dose adjustment is required for patients taking protease inhibitors.

As a class, protease inhibitors (PIs) are the antiretroviral agents most strongly implicated in kidney toxicity. [1] PIs (ie, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, lopinavir, atazanavir, tipranavir, darunavir) may precipitate nephrolithiasis. A classic form of this is crystalluria with the older agent indinavir, which occurs independently of kidney function; however, the stones resolve after cessation of indinavir therapy. A study by Rockwood et al found that the rate of kidney stones was 7.3 per 1000 patient-years in patients receiving ritonavir-boosted atazanavir compared with 1.9 per 1000 patient years in patients receiving other commonly used antivirals. [19]

Enfuvirtide (Fuzeon) is the first of a newer class of fusion inhibitors that targets the gp41 protein on the surface of HIV and stops the virus from entering cells. Enfuvirtide has no known renal effects in patients with creatinine clearance of greater than 35 mL/min.

Maraviroc (Selzentry) is also a fusion inhibitor. It blocks the CCR5 coreceptor on CD4+ cells, preventing the virus from entering. Maraviroc does not require dose adjustment for creatinine clearance greater than 50 mL/min.

Raltegravir (Isentress) is the first of a newer class of integrase strand transfer inhibitors. It does not require dose adjustment in patients with abnormal kidney function.

A complete list of HIV drug classes and antiretroviral regimens can be found at HIV Drug Chart.

Some drugs used to treat opportunistic infections in HIV disease may also cause nephrotoxicity or electrolyte abnormalities (see the image below).

Types of electrolyte abnormalities observed with s Types of electrolyte abnormalities observed with some of the drugs used to treat opportunistic infections in patients with human immunodeficiency virus (HIV). ARF stands for acute renal failure.

Pharmacologic Therapy

Although there are no guiding clinical studies, some experts recommend consideration of therapy in all patients with HIV-associated nephropathy (HIVAN). Initiation or adjustment of antiretroviral therapy may be indicated. See Antiretroviral Therapy for HIV Infection for specific information, including recommendations for dosage adjustments for kidney insufficiency.

Angiotensin-converting enzyme (ACE) inhibitors and corticosteroids have been studied for use in HIVAN. Some reports on pediatric populations suggest that cyclosporine can be effective in reducing proteinuria in persons with HIVAN. The usefulness of cyclosporine therapy for HIVAN warrants further study. Researchers are pursuing several promising therapeutic strategies. Patients who progress to end-stage renal disease (ESRD) require dialysis and consideration of kidney transplantation in carefully selected cases.

Angiotensin-converting enzyme inhibitors

In patients with advanced kidney insufficiency, captopril was noted to improve renal survival for a mean length of 37-156 days. [20] In a subsequent prospective follow-up of 44 patients, the median length of renal survival for patients who received fosinopril was 479.5 days, with only 1 patient developing ESRD. All untreated control subjects progressed to ESRD, with a median length of renal survival of 146.5 days. [21]

The exact mechanism of action of ACE inhibitors in HIVAN is unknown, but it may be related to a hemodynamic effect, a reduction in the transglomerular passage of serum proteins, and an antiproliferative effect mediated in part by the inhibition of transforming growth factor beta. Use ACE inhibitors if patients do not have hyperkalemia.


A number of case reports have suggested that corticosteroids offer some short-term benefit in HIVAN. [22] In one report, results from a pretreatment and posttreatment kidney biopsy suggested that an improvement in kidney function was associated with a reduced number of lymphocytes and macrophages infiltrating the interstitium.

In another report, of 20 patients who were treated with prednisone, 60 mg/day for 2 weeks to 11 weeks, followed by a slow taper, [23] 8 patients required maintenance dialysis, 11 died from complications, and 7 were alive and no longer had ESRD after a follow-up of 44 weeks.


End-Stage Renal Disease

Persons with well-controlled HIV infection and ESRD are candidates for both hemodialysis and peritoneal dialysis and should be evaluated for kidney transplantation. Early discussion and planning is important so that use of hemodialysis catheters can be avoided, as HIV-infected persons are at similar, if not higher, risk for infection and other complications related to catheter use. [1] Although large studies demonstrate a clear benefit of organ transplantation for HIV-postive patients with ESRD, HIV-positive patients experience high rates of acute allograft rejection. 

Immunosuppression after kidney transplantation is thought to pose a substantive risk of opportunistic infections in patients with HIVAN. [24] Consequently, kidney transplantation in these patients is performed with caution in compliant, stable patients with no prior opportunistic infections who have an undetectable viral load and a CD4+ T-cell count of more than 300 cells/µL. However, anecdotal reports drawn from small samples of selected patients with HIVAN suggest no extra risk of opportunistic infections. Until larger studies are performed, transplantation in persons with HIVAN should be focused on stable patients. [25]

Given the strong association between the APOL1 risk variants and HIVAN, HIV-positive recipients of African descent and those who receive an allograft from a donor of African descent should be monitored for recurrent HIVAN. The relative contribution of donor and recipient APOL1 risk status to the risk of HIVAN recurrence is the subject of ongoing research. [5]   

Access to kidney transplantation remains limited and HIV-positive individuals face disproportionately higher mortality while on the transplant waitlist. [26] A study of a dataset comprising 23,414 patients, 469 of whom were HIV positive, who received dialysis in 2012-2016, found that the HIV-positive patients with ESRD waited longer for kidney transplantation referral, evaluation, and waitlisting than HIV-negative patients. [27]  

The HIV Organ Policy Equity (HOPE) Act, which was signed into law in 2013 and had its guidelines finalized in 2015, permits transplantation using organs from HIV-positive donors to HIV-positive recipients in the United States. [28] This approach has the potential to reduce the wait time for kidney transplantation for HIV-positive persons, which may exceed 5 years in some urban areas. [29]


Questions & Answers


What are HIV-related renal disorders?

What is the pathologic classification of HIV-related renal disorders?

What is HIV-associated nephropathy (HIVAN)?

What is the pathophysiology of HIV-associated nephropathy (HIVAN)?

What is the role of genetics in the etiology of HIV-related renal disorders?

What is the prevalence of HIV-related renal disorders?

What is the prognosis of HIV-related renal disorders following kidney transplantation?

How is HIV-associated nephropathy (HIVAN) treated?

What is the role of ACE inhibitors in the treatment of HIV-associated nephropathy (HIVAN)?

What is the role of corticosteroids in the treatment of HIV-associated nephropathy (HIVAN)?

How is HIV-related ESRD treated?

When is kidney transplantation indicated for the treatment of HIV-associated nephropathy (HIVAN)?

How is the wait time for kidney transplantation being reduced for HIV-related renal disorders?

Which clinical history findings are characteristic of HIV-associated nephropathy (HIVAN)?

How does the CD4+ T-cell count affect the prognosis of HIV-associated nephropathy (HIVAN)?

Which findings on imaging studies are characteristic of HIV-associated nephropathy (HIVAN)?

Which urinalysis findings are characteristic of HIV-associated nephropathy (HIVAN)?

What causes electrolyte abnormalities in HIV-associated nephropathy (HIVAN)?

What causes SIADH in HIV-associated nephropathy (HIVAN)?

What is the role of renal biopsy in the diagnosis of HIV-associated nephropathy (HIVAN)?

Which histologic findings are characteristic of HIV-associated nephropathy (HIVAN)?

What is the role of antiretroviral drugs in the etiology of HIV-related renal disorders?

Which drugs used to treat opportunistic infections in HIV cause nephrotoxicity?