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Infectious Disorders - Drug Targets


ISSN (Print): 1871-5265
ISSN (Online): 2212-3989

Research Article

Effects of Highly Active Antiretroviral Therapy on Renal Function and Renal Phosphate Handling in African Adults with Advanced HIV and CKD

Author(s): Tewogbade A. Adedeji*, Simeon A. Adebisi, Nife O. Adedeji, Sikiru A. Biliaminu and Timothy O. Olanrewaju

Volume 19 , Issue 1 , 2019

Page: [88 - 100] Pages: 13

DOI: 10.2174/1871526518666180720115240

Price: $65


Background: Highly Active Antiretroviral Therapy (HAART) has been implicated in renal dysfunction with hypophosphataemia.

Objective: We prospectively evaluated renal phosphate excretion during HAART use.

Method: Newly diagnosed human immunodeficiency virus (HIV)-infected individuals were treated with Tenofovir disoproxil fumarate/Emtricitabine/Efavirenz (TDF/FTC/EFV), n=33; Zidovudine/Lamivudine/Nevirapine (ZDV/3TC/NVP), n=53; and Zidovudine/Lamivudine/Efavirenz (ZDV/3TC/EFV), n=16. Creatinine and phosphate were assayed in blood and urine simultaneously at baseline, 1, 3, 6 and 9 months. Glomerular filtration rate (eGFR), fractional phosphate excretion and reabsorption (FEPi % and TRP), and the ratio of tubular maximum reabsorption of phosphate (TmP) to GFR (TmP/GFR) were estimated.

Results: At baseline, eGFR showed moderate chronic kidney disease (mean: 35.50 ± 2.02, 33.14 ± 1.63, and 39.97±1.84 ml/min/1.73m2 in the 3 groups respectively); 54 (52.9%) patients had hyperphosphataemia (>1.4mmo/L); 43 (42.2%) had normophosphataemia (0.6-1.4mmol/L); 5 (4.9%) had hypophosphataemia (<0.6mmol/L). eGFR improved significantly from 1 month (≥60, 58.65 ± 1.11, and 51.76 ±1.59 ml/min/1.73m2; p=0.04, <0.001, 0.67 respectively), with a relapse at 9 months in TDFtreated subjects (50.10 ± 1.89 ml/min/1.73m2). TDF/FTC/EFV resulted in significantly greater reduction in plasma phosphate than ZDV/3TC/NVP (p=0.031), but not significantly different from ZDV/3TC/EFV (p=0.968). Similarly, ZDV/3TC/EFV resulted in significantly greater reduction in plasma phosphate than ZDV/3TC/NVP (p=0.036).

FEP% progressively increased with HAART duration, more in TDF-treated and ZDV/3TC/EFV-treated groups than ZDV/3TC/NVP (p=0.014); TRP was elevated (>0.86), implying non-maximal phosphate reabsorption. TmP/GFR values were elevated, (>1.35mmol/l).

Conclusion: HIV causes kidney dysfunction with reduced phosphate excretion resulting in hyperphosphataemia but HAART improves renal function. Prolonged use of TDF can cause renal toxicity with hypophosphataemia as fractional excretion progressively increased with duration of therapy unlike ZDV/3TC/NVP. The use of different third agents (either NVP or EFV) in zidovudine-based therapy results in significantly different plasma phosphate levels; ZDV/3TC/EFV, like TDF/FTC/EFV, resulted in significantly greater decline in plasma phosphate than ZDV/3TC/NVP. Thus, Evafirenz (EVF) may have similar or synergistic adverse effects with tenofovir disoproxil fumarate (TDF).

Keywords: Highly active antiretroviral therapy, human immunodeficiency virus, hyperphosphataemia, hypophosphataemia, renal function, renal handling of phosphate.

Graphical Abstract
Walmsley, R.N.; and Guerin, M.D. Renal Disease. In: Disorders of fluid and electrolyte balance; Bristol: John Wright, 1984; pp. 153-160.
Endres, D.B.; Rude, R.K. Mineral and bone metabolism. In: Teitz textbook of clinical chemistry; Burtis, C.A.; Ashwood, E.R., Eds.; Philadelphia: W. B. Saunders, 1999; pp. 1905-1908.
Crook, M.A. Calcium, Phosphate, and Magnesium. Clinical chemistry and metabolic medicine, 2006, 215.
Klotman, P.E. HIV-associated nephropathy. Kidney Int., 1999, 56(3), 1161-1176.
Gutierrez, O.; Isakova, T.; Rhee, E.; Shah, A.; Holmes, J.; Collerone, G.; Jüppner, H.; Wolf, M. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J. Am. Soc. Nephrol., 2005, 16(7), 2205-2215.
Yu, G.C.; Lee, D.B.N. Clinical disorders of phosphorus metabolism. West. J. Med., 1987, 147(5), 569-576.
Knochel, J.P.; Jacobson, H.R. Renal handling of phosphorus in health and disease. The Kidney, 1986, 619-662.
Payne, R.B. Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation. Ann. Clin. Biochem., 1998, 35(Pt 2), 201-206.
Izzedine, H.; Hulot, J.S.; Vittecoq, D.; Gallant, J.E.; Staszewski, S.; Launay-Vacher, V.; Cheng, A.; Deray, G. Long-term renal safety of tenofovir disoproxil fumarate in antiretroviral-naive HIV-1-infected patients. Data from a double-blind randomized active-controlled multicentre study. Nephrol. Dial. Transplant., 2005, 20(4), 743-746.
Day, S.L.; Leake Date, H.A.; Bannister, A.; Hankins, M.; Fisher, M. Serum hypophosphatemia in tenofovir disoproxil fumarate recipients is multifactorial in origin, questioning the utility of its monitoring in clinical practice. J. Acquir. Immune Defic. Syndr., 2005, 38(3), 301-304.
Reynes, J.; Peyriere, H.; Merle de Boever, C.; Le Moing, V. Renal tubular injury and severe hypophosphataemia (Fanconi Syndrome) associated with tenofovir therapy. Proceedings of the 10th Conference on Retroviruses and Opportunistic infections, 2003 Feb 11- 14Boston, USA
Thompson, M.A.; Aberg, J.A.; Cahn, P.; Montaner, J.S.; Rizzardini, G.; Telenti, A.; Gatell, J.M.; Günthard, H.F.; Hammer, S.M.; Hirsch, M.S.; Jacobsen, D.M.; Reiss, P.; Richman, D.D.; Volberding, P.A.; Yeni, P.; Schooley, R.T. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA, 2010, 304(3), 321-333.
Barth, J.H.; Jones, R.G.; Payne, R.B. Calculation of renal tubular reabsorption of phosphate: the algorithm performs better than the nomogram. Ann. Clin. Biochem., 2000, 37(Pt 1), 79-81.
Walton, R.J.; Bijvoet, O.L.M. Nomogram for derivation of renal threshold phosphate concentration. Lancet, 1975, 2(7929), 309-310.
Pitisci, L.; Demeester, R.; Legrand, J.C. Prevalence and European AIDS Clinical Society (EACS) criteria evaluation for proximal renal tubular dysfunction diagnosis in patients under antiretroviral therapy in routine setting. J. Int. AIDS Soc., 2014, 17(4)(Suppl. 3), 19564.
Hall, A.M.; Hendry, B.M.; Nitsch, D.; Connolly, J.O. Tenofovir-associated kidney toxicity in HIV-infected patients: a review of the evidence. Am. J. Kidney Dis., 2011, 57(5), 773-780.
Gerntholtz, T.E.; Goetsch, S.J.W.; Katz, I. HIV-related nephropathy: a South African perspective. Kidney Int., 2006, 69(10), 1885-1891.
Cohen, A.H.; Sun, N.C.J.; Shapsak, P. Demonstration of HIV in renal epithelium in HIV-associated nephropathy. Mod. Pathol., 1989, 2(2), 125-128.
Bruggeman, L.A.; Ross, M.D.; Tanji, N.; Cara, A.; Dikman, S.; Gordon, R.E.; Burns, G.C.; D’Agati, V.D.; Winston, J.A.; Klotman, M.E.; Klotman, P.E. Renal epithelium is a previously unrecognized site of HIV-1 infection. J. Am. Soc. Nephrol., 2000, 11(11), 2079-2087.
Kimmel, P.L.; Ferreira-Centeno, A.; Farkas-Szallasi, T.; Abraham, A.A.; Garrett, C.T. Viral DNA in microdissected renal biopsy tissue from HIV infected patients with nephrotic syndrome. Kidney Int., 1993, 43(6), 1347-1352.
Pardo, V.; Aldana, M.; Colton, R.M.; Fischl, M.A.; Jaffe, D.; Moskowitz, L.; Hensley, G.T.; Bourgoignie, J.J. Glomerular lesions in the acquired immunodeficiency syndrome. Ann. Intern. Med., 1984, 101(4), 429-434.
Rao, T.K.; Filippone, E.J.; Nicastri, A.D.; Landesman, S.H.; Frank, E.; Chen, C.K.; Friedman, E.A. Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N. Engl. J. Med., 1984, 310(11), 669-673.
Winston, J.A.; Bruggeman, L.A.; Ross, M.D.; Jacobson, J.; Ross, L.; D’Agati, V.D.; Klotman, P.E.; Klotman, M.E. Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. N. Engl. J. Med., 2001, 344(26), 1979-1984.
Weiner, N.J.; Goodman, J.W.; Kimmel, P.L. The HIV-associated renal diseases: current insight into pathogenesis and treatment. Kidney Int., 2003, 63(5), 1618-1631.
Kopp, J.B.; Winkler, C. HIV-associated nephropathy in African Americans. Kidney Int. Suppl., 2003, (83), S43-S49.
Stehman-Breen, C.O.; Gillen, D.; Steffes, M.; Jacobs, D.R., Jr; Lewis, C.E.; Kiefe, C.I.; Siscovick, D. Racial differences in early-onset renal disease among young adults: the coronary artery risk development in young adults (CARDIA) study. J. Am. Soc. Nephrol., 2003, 14(9), 2352-2357.
Chemlal, K.; Nochy, D.; Kenouch, S.; Joly, V.; Carbon, C. Dramatic improvement of renal dysfunction in a human immunodeficiency virus-infected woman treated with highly active antiretroviral therapy. Clin. Infect. Dis., 2000, 31(3), 805-806.
Gallant, J.E.; Parish, M.A.; Keruly, J.C.; Moore, R.D. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin. Infect. Dis., 2005, 40(8), 1194-1198.
Mauss, S.; Berger, F.; Schmutz, G.; Stefan, F. Antiretroviral therapy with tenofovir is associated with mild renal dysfunction. AIDS, 2005, 19(1), 93-95.
Waheed, S.; Attia, D.; Estrella, M.M.; Zafar, Y.; Atta, M.G.; Lucas, G.M.; Fine, D.M. Proximal tubular dysfunction and kidney injury associated with tenofovir in HIV patients: a case series. Clin. Kidney J., 2015, 8(4), 420-425.
Wanner, D.P.; Tyndall, A.; Walker, U.A. Tenofovir-induced osteomalacia. Clin. Exp. Rheumatol., 2009, 27(6), 1001-1003.
Slocum, J.L.; Heung, M.; Pennathur, S. Marking renal injury: can we move beyond serum creatinine? Transl. Res., 2012, 159(4), 277-289.
Buchacz, K.; Brooks, J.T.; Tong, T. 2006.XVI International AIDS Conference,
Gallant, J; Pozniak, A; Staszewski, S; Lu, B. Similar 96- week renal safety profile of tenofovir DF versus stavudine (d4T) when used in combination with lamivudine and efavirenz in antiretroviral naïve patients. 43rd ICAAC, Chicago, USA 2003, Abstract H- 840.
Cirillo, M.; Ciacci, C.; De Santo, N.G. Age, renal tubular phosphate reabsorption, and serum phosphate levels in adults. N. Engl. J. Med., 2008, 359(8), 864-866.

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