Abstract
With the introduction of potent combination antiretroviral therapy (cART) into clinical practice, HIV-infected patients have garnered much benefit. However, kidney disease continues to be a potential complication in this group. Whereas HIV-associated nephropathy (HIVAN) was the major renal complication prior to cART, co-morbid diseases and adverse renal effects of various drugs, in particular cART, now complicate the landscape. Clinicians now must differentiate HIVAN from cART nephrotoxicity. While sometimes this is easy and relatively straightforward, often the clinician faces a difficult challenge distinguishing these two etiologies of kidney disease. This review will discuss HIVAN and cART-related kidney disease and review the clinical and laboratory data that may be useful in differentiating these processes. Often, however, kidney biopsy may be required to differentiate HIVAN from cART nephrotoxicity as well as other kidney lesions associated with concurrent co-morbidities, both infectious and non-infectious.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Fine DM, Perazella MA, Lucas GM, et al. Kidney biopsy in HIV: beyond HIV-associated nephropathy. Am J Kidney Dis. 2008;51(3):504–14.
Rao TK, Filippone EJ, Nicastri AD, et al. Associated focal and segmental glomerulosclerosis. N Engl J Med. 1984;310:669–73.
Ross MJ, Klotman PE. Recent progress in HIV-associated nephropathy. J Am Soc Nephrol. 2002;13:2997–3004.
Herman ES, Klotman PE. HIV- associated nephropathy: epidemiology, pathogenesis, and treatment. Semin Nephrol. 2003;23(2):200–8.
Abbot KC, Hypolite J, Welch PT, et al. Human immunodeficiency virus/acquired immunodeficiency syndrome associated nephropathy at end stage renal disease in the United States: patient characteristics and survival in the pre highly active retroviral therapy era. J Nephrol. 2001;14:377–83.
Mallipattu SK, Wyatt CM, He JC. The new epidemiology of HIV-related kidney disease. J AIDS Clin Res. 2012;S4:1–6. This article describes the changing epidemiology of HIV in both the pre and post- cART era. It focuses on the racial predilection of HIV and its association with diabetes, hypertension and co-infection with hepatitis C.
Berliner AR, Fine DM, Lucas GM, et al. Observations on a cohort of HIV-infected patients undergoing native renal biopsy. Am J Nephrol. 2008;28:478–86.
Wyatt CM, Meliambro K, Klotman PE. Recent progress in HIV- associated nephropathy. Ann Rev Med. 2012;63:147–59. This comprehensive review highlights the advances in HIV disease epidemiology and pathogenesis with specific focus on genetic predisposition and treatment.
Bruggeman LA, Ross MD, Tanji N, et al. Renal epithelium in a previously unrecognized site of HIV-1 infection. J Am Soc Nephrol. 2000;11(11):2079–87.
Winston JA, Bruggeman LA, Ross MD, et al. Nephropathy and establishment of a renal resevoir of HIV type 1 during primary infection. N Engl J Med. 2001;344:1979–84.
Medapalli RK, He JC, Klotman PE. HIV- associated nephropathy: pathogenesis. Curr Opin Nephrol Hypertens. 2011;20(3):306–11.
Atta MG. Diagnosis and natural history of HIV-associated nephropathy. Adv Chronic Kidney Dis. 2010;17(1):52–8.
Kopp JB, Smith MW, Nelson GW, et al. MYH9 is a major effect risk gene for focal segmental glomerulosclerosis. Nat Genet. 2008;40:1175–84.
Kaufman L, Collins SE, Klotman PE. The pathogenesis of HIV-associated nephropathy. Adv Chronic Kidney Dis. 2010;17(1):36–43.
Genovese G, Friedman DJ, Ross MD, et al. Association of Trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010;329:841–5.
Ross MJ, Klotman PE, Winston JA. HIV-associated nephropathy: case study and review of the literature. AIDS Patient Care STDs. 2000;14:637–45.
Atta MG, Choi MJ, Longnecker JC, et al. Nephrotic range proteinuria and CD4 count as noninvasive indicators of HIV-associated nephropathy. Am J Med. 2005;118:1288.e21–6.
Han TM, Naicher S, Ramdial PK, et al. A cross-sectional study of HIV-seropositive patients with varying degrees of proteinuria in South Africa. Kidney Int. 2006;69(12):2243–50.
Estrella M, Fine DM, Gallant JE, et al. HIV type 1 RNA level as a clinical indicatory of renal pathology in HIV-infected patients. Clin Infect Dis. 2006;43:377–80.
Atta MG, Longenecker JC, Fine DM, et al. Sonography as a predictor of human immunodeficiency virus-associated nephropathy. J Ultrasound Med. 2004;23:603–10.
Atta MG, Gallant JE, Rahman MH, et al. Antiretroviral therapy in the treatment of HIV-associated nephropathy. Nephrol Dial Transplant. 2006;21:2809–13.
D’agati V, Appel GB. HIV infection and the kidney. J Am Soc Nephrol. 1997;8:138–52.
Lau B, Gange SJ, Moore RD. Risk of non-AIDS related mortality may exceed risk of AIDS related mortality among individuals enrolling in care with CD4+ counts greater than 200cells/mm3. J AIDS. 2007;44:179–87.
Winston J, Deray G, Hawkins T, et al. Kidney disease in patients with HIV infection and AIDS. Clin Infect Dis. 2008;47(11):1449–57.
Roling J, Schmid H, Fischereder M, et al. HIV- associated renal diseases and highly active antretroviral therapy-induced nephropathy. Clin Infect Dis HIV/AIDS. 2006;42:1488–95.
Herman JS, Ives NJ, Nelson M, et al. Incidence and risk factors for the development of indinavir- associated renal complications. J Antibicrobial Chemother. 2001;48:355–60.
Dielman JP, Sturkenboom MC, Jambroes M, et al. Risk factors for urological symptoms in a cohort of users of the HIV protease inhibitor indinavir sulfate: the ATHENA cohort. Arch Intern Med. 2002;162:1493–501.
Sarcletti M, Petter A, Romani N, et al. Pyuria in patients treated with indinavir is associated with renal dysfunction. Clin Nephrol. 2000;54:261–70.
Kopp JB, Miller KD, Mican JA, et al. Crystalluria and urinary tract abnormalities associated with indinavir. Ann Intern Med. 1997;127:119–25.
Kopp J, Falloon J, Fillie A, et al. Indinavir-associated interstitial nephritis and urothelial inflammation: clinical and cytologic findings. Clin Infect Dis. 2002;99:1122–8.
Valle R, Haragsim L. Nephrotoxicity as a complication of antiretroviral therapy. Adv Chronic Kidney Dis. 2006;23(3):314–9.
Couzigou C, Daudon M, Meynard JL, et al. Urolithiasis in HIV-positive patients treated with Atazanvir. Clin Infect Dis Brief Rep. 2007;45:e105–8.
Chan-Tack KM, Truffa MM, Struble KA, et al. Atazanavir- associated nephrolithiasis: cases from the US Food and Drug Administration’s adverse event reporting system. AIDS. 2007;21(9):1251–8.
Hamda Y, Nishijima T, Watanabe K, et al. High incidence of renal stones among HIV-infected patients on ritonavir-boosted atazanavir than in those receiving other protease inhibitor-contating atiretroviral therapy. Clin Infect Dis. 2012;55(9):1262–9. This single center study evaluated the incidence of nephrolithiasis associated with atazanavir and a ritonavir boost and noted it was significantly higher compared to patients who were on other protease inhibitors. Furthermore, renal stones were associated with high recurrence if this combination therapy was continued.
Brewster UC, Perazella MA. Acute interstitial nephritis associated with atazanavir, a new protease inhibitor. Am J Kidney Dis. 2004;44(5):e81–4.
Schmid S, Opravil M, Moddel M, et al. Acute interstitial nephritis of HIV-positive patients under atazanavir and tenofovir therapy in a retrospective analysis of kidney biopsies. Virchows Arch. 2007;450(6):665–70.
Izzedine H, M’rad MB, Bardier A, et al. Atazanavir crystal nephropathy. AIDS. 2007;21(17):2357–8.
Viglietti D, Verine J, De Castro N, et al. Chronic interstitial nephritis in an HIV type-1-infected patient receiving ritonavir-boosted atazanavir. Antivir Ther. 2011;16(1):119–21.
Rasch MG, Engsig FN, Feldt-Rasmussen B, et al. Renal function and incidence of chronic kidney disease in HIV patients: a Danish cohort study. Scand J Infect Dis. 2012;44(9):689–96. This large Scandanavian cohort study evaluated the development and progression of chronic kidney disease among patients with HIV taking cART. The study concluded that certain drugs (tenofovir and indinavir) result in decreased kidney function and increase the risk of CKD.
Gupta SK. Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system. AIDS Patient Care STDS. 2008;22(2):99–103.
Gallant JE, Parish MA, Kerule JE, et al. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis. 2005;40(8):1194–8.
Coca S, Perazella MA. Rapid communication: acute renal failure associated with tenofovir: evidence of drug induced nephropathy. Am J Med Sci. 2002;324(6):342–4.
Creput C, Gonzalez-Canali G, Hill G, et al. Renal lesions in HIV-1 positive patient treated with tenofovir. AIDS. 2003;17(6):935–7.
Karras A, Lafaurie M, Furco A, et al. Tenofovir- related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis. 2003;36:1070–3.
Verhelst D, Monge M, Meynard JL, et al. Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am J Kidney Dis. 2002;40(6):1331–3.
Jao J, Wyatt CM. Antiretroviral medications: adverse effects on the kidney. Adv Chronic Kidney Dis. 2010;17(1):72–82.
Kalyesubula R, Perazella MA. Nephrotoxocity of HAART. AIDS Res Treat. 2011;2011:562790. This article described renal toxicity associated with antiretroviral drugs including acute tubular necrosis, acute interstitial nephritis, crystal nephropathy and renal tubular disorders. Additionally, it focused on risk factors associated with these toxicities as well as prevention and prevention strategies.
Cihlar T, Ho ES, Lin DC, Mulato AS. Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides Nucleic Acids. 2001;20:641–8.
Gitman MD, Hirschwerk D, Baskin CH, et al. Tenofovir-induced kidney injury. Expert Opin Drug Saf. 2006;6(2):155.162.
Nishijima T, Komatsu H, Higasa K, et al. Single nucleotide polymorphisms in ABCC2 associate with tenofovir- induced kidney tubular dysfunction in Japanese patients with HIV-1 infection: a pharmacogenetic study. Clin Infect Dis. 2012;55(11):1558–67.
Perazella MA. Tenofovir- induced kidney disease: an acquired renal tubular mitochondriopathy. Kidney Int. 2010;78(11):1060–3.
Herlitz LC, Mohan S, Stokes MB, et al. Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities. Kidney Int. 2010;78:1171–7.
Mauss S, Berger F, Schmutz G. Antiretroviral therapy with tenofovir is associated with mild renal dysfunction. AIDS. 2005;19:93–5.
Gallant J. Modest decline in renal function associated with tenofovir compared to NRTI treatment. 12th conference on retroviruses and opportunistic infections, Boston, February 2005: 22-25.
Fux C, Simcock M, Wolbers M, et al. Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV cohort study. Antivir Ther. 2007;12:1165–73.
Young B, Buchacz K, Baker R, et al. Renal function in tenofovir- exposed and tenofovir-unexposed patients receiving highly active retroviral therapy in the HIV outpatient study. J Int Assoc Physician AIDS. 2007;6:178–87.
Scherzer R, Estrella M, Li Y, et al. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS. 2012;26:1–9. This large trial conducted at the Veteran’s Health Administration evaluated renal outcomes in patients on tenofovir. Exposure to this drug increased risk for proteinuria and chronic kidney disease. Interestingly, other traditional risk factors did not produce worse outcomes and discontinuation of tenofovir did not decrease risk of renal disease in follow up.
Elias A, Ijeoma O, Edikpo J, et al. Tenofovir renal toxitity: evaluation of cohorts and clinical studies- part 2. Pharmacol Pharm. 2014, available at http://www.scirp.org/journal/pp) doi:10.4236/pp.2014.51015.
Compliance with Ethics Guidelines
Conflict of Interest
Neelja Kumar and Mark A. Perazella declare that they have no conflict of interest
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kumar, N., Perazella, M.A. Differentiating HIV-associated Nephropathy from Antiretroviral Drug-Induced Nephropathy: A Clinical Challenge. Curr HIV/AIDS Rep 11, 202–211 (2014). https://doi.org/10.1007/s11904-014-0209-9
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11904-014-0209-9