Nephropathy, HIV-Associated (HIVAN)
- HIVAN is an aggressive, collapsing form of focal segmental glomerulosclerosis (FSGS) with active tubulointerstitial inflammation.
- At least 1 glomerulus with collapse of glomerular basement membranes should be present accompanied by hypertrophy and hyperplasia of the overlying glomerular epithelial cells.
- Active tubulointerstitial nephritis is manifest as microcytic tubular dilatation, interstitial inflammation, and tubular injury.
- Nephrotic-range proteinuria may be massive and predate renal insufficiency.
- Rapid progression to ESRD may occur without treatment.
- Strong genetic predisposition, predominance in patients of African ancestry. Apolipoprotein L1 (APOL1) gene renal risk variants, G1 and G2, are associated with focal segmental glomerular sclerosis, especially collapsing subtype.
- Other risk factors: low CD4 cell count, high HIV viral load, and family history of renal disease.
- Presents in AIDS-defining, late-stage illness (CD4< 200) or during acute HIV infection.
- Biopsy is gold standard for diagnosis. Other markers (eg, proteinuria, CD4, VL) are nonspecific.
- Proteinuria, urinalysis typically bland; nephritic profile suggests alterntive diagnosis.
- Urgent renal biopsy indicated for significant proteinuria (>1g/24h), increasing proteinuria, decreasing GFR, or unexplained acute or subacute renal failure.
- Pathognomonic features: FSGS, collapsing variant; interstitial inflammation +/- fibrosis; microcystic tubular dilatation; tubuloreticular inclusions on EM.
- Renal ultrasound: echogenic kidneys of normal-to-enlarged size.
- Without biopsy, DDx includes: primary FSGS, immune complex glomerulonephritis (GN), hepatitis B or C-assocaited GN, drug-induced interstitial nephritis, amyloidosis, IgA nephropathy, injection drug use nephrotoxicity, thrombotic microangiopathy, ATN. Collapsing glomerulopathy is described in SARS-CoV-2 infection.
- Assessment of kidney function:
- Measure eGFR at ART initiation or change, and at least twice yearly in those with viral suppression.
- Individuals of African ancestry with CD4< 200, high VL, DM, HTN, hepatitis B or C, or family history of kidney disease are at greater risk for kidney damage. Additional risk factors include cocaine use, cigarette use, or dyslipidemia.
- Assessment of kidney damage:
- Urinalysis or quantitative measure of albuminuria/proteinuria at baseline, at ART initiation or change, and at least annually in PLWH.
- Proteinuria ≥1+ on dipstick, clinically significant albuminuria >300 mg/day (nondiabetics) OR >30 mg/day (diabetics), GFR decline >25% from baseline, or GFR < 60ml/min/1.73m2 merits renal ultrasound, early referral to nephrologist, and renal biopsy.
Approach to therapy
- Immediate ART most likely to reverse or stabilize renal dysfunction, prevent progression, and improve long-term renal function and survival outcomes.
- BP should be kept < 130/80 with use of ACE inhibitors or angiotensin receptor blockers (ACEi/ARB) since they may reverse proteinuria and renal insufficiency and prevent progression to ESRD.
- Corticosteroids adjunct to ART +/- ACEi/ARB. Initial response may be dramatic, even reversing dialysis dependence, but transient.
- Preserve venous access by avoiding peripherally inserted central venous catheters and subclavian central venous catheters in those who may need permanent hemodialysis access.
- Blood glucose control in those with DM.
- Review all medications including over-the-counter medications, i.e., NSAIDS, for those with renal toxicity or those requiring renal dose-adjustment.
- Initiate ART
Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptors blockers (ARBs)
- Antiproteinuric and reno-protective properties are independent of antihypertensive effect.
- Reduce rate of progression of proteinuria and nephropathy
- May cause or exacerbate hyperkalemia
- Observational data suggest corticosteroid therapy can rapidly, but transiently, reverse HIVAN.
- Prednisone 1 mg/kg (up to 80 mg PO qd) for 2 mo, then tapered over 2-4 mos
- Exclude opportunistic infections (OIs) before initiating corticosteroids and remain vigilant for new OIs.
- Monitor serum creatinine and spot urine protein/creatinine ratio.
Basis for recommendation
- Lucas GM, Ross MJ, Stock PG, et al. Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(9):e96-138. [PMID:25234519]
Comment: HIV Medicine Association of IDSA clinical practice guidelines detail diagnostics for evaluation of HIV-related chronic kidney disease. Routine screening includes eGFR by CKD-EPI creatinine equation or the Cockcroft-Gault equation and urinalysis or quantitative measure of albuminuria/proteinuria. In those patients with GFR < 60, avoidance of tenofovir recommended.
- Goyal R, Singhal PC. APOL1 risk variants and the development of HIV-associated nephropathy. FEBS J. 2021;288(19):5586-5597. [PMID:33340240]
Comment: APOL1 gene renal risk variants (G1 and G2), found commonly in African populations, are associated with focal segmental glomerular sclerosis, especially collapsing subtype.
- Velez JCQ, Caza T, Larsen CP. COVAN is the new HIVAN: the re-emergence of collapsing glomerulopathy with COVID-19. Nat Rev Nephrol. 2020;16(10):565-567. [PMID:32753739]
Comment: Collapsing glomerulopathy characterized in setting of HIV infection is described in association with SARS-CoV-2 infection. Of note, authors invoke activation of interferon and chemokines rather than direct infection of glomerular cells.
- Menez S, Hanouneh M, McMahon BA, et al. Pharmacotherapy and treatment options for HIV-associated nephropathy. Expert Opin Pharmacother. 2018;19(1):39-48. [PMID:29224373]
Comment: Comprehensive review of HIVAN to date includes comment on kidney transplant outcomes in PLWH. Given rapid progression to ESRD, authors emphasize prevention and include ART, renin-angiotensin-aldosterone system (RAAS) blockade and prednisone as treatment options.
- Scherzer R, Gandhi M, Estrella MM, et al. A chronic kidney disease risk score to determine tenofovir safety in a prospective cohort of HIV-positive male veterans. AIDS. 2014;28(9):1289-95. [PMID:24922479]
Comment: Based on VA data of 21,590 HIV+ men, authors developed CKD risk score to predict absolute 5-year risk of developing CKD, defined as two consecutive measurements of eGFR < 60 at least 3 months apart and not obtained during inpatient admissions. Risk factors included: age, glucose >140, SBP >140, HTN, TG >200, proteinuria >30mg/dl, and CD4 < 200. After controlling for risk factors via risk score, overall RR of CKD was two-fold higher in TDF ever vs never users.
- Lucas GM, Jing Y, Sulkowski M, et al. Hepatitis C viremia and the risk of chronic kidney disease in HIV-infected individuals. J Infect Dis. 2013;208(8):1240-9. [PMID:23904290]
Comment: NA-ACCORD study of 93,495 HIV+ people in US and Canada compared CKD incidence in HCV seronegative, HCV viremic, and HCV aviremic participants. HCV seropositive pts with or without viremia were at increased risk for CKD.
- Yahaya I, Uthman OA, Uthman MM. Interventions for HIV-associated nephropathy. Cochrane Database Syst Rev. 2013;1:CD007183. [PMID:23440812]
Comment: Analytical review supports ART to treat HIVAN with evidence to support improvement in kidney function associated with VL suppression. Adjunct treatment includes avoidance of nephrotoxins, routine measurement of eGFR, and assessment for proteinuria.
- Wyatt CM, Meliambro K, Klotman PE. Recent progress in HIV-associated nephropathy. Annu Rev Med. 2012;63:147-59. [PMID:21888512]
Comment: Epidemiology-focused review of HIVAN notes contribution of both host genetic attributes, e.g., APOL1 and MYH9 alleles, and pathogenicity of HIV. ART initation indicated to improve kidney function. Renal transplant is an alternative to dialysis in well-controlled HIV infection.
- Wyatt CM. The kidney in HIV infection: beyond HIV-associated nephropathy. Top Antivir Med. 2012;20(3):106-10. [PMID:22954611]
Comment: Reduced rates of HIVAN, due to increased numbers of PLWH achieving viral suppression on ART, expose hypertension and diabetes as cause of chronic kidney disease.