Renal Phosphate Handling in Antiretroviral-naive HIV-Infected Patients

Tewogbade    Adeoye    Adedeji; Simeon    Adelani    Adebisi; Nife    Olamide    Adedeji; Olusola    Akanni    Jeje; Rotimi    Samuel    Owolabi

doi:10.2174/1871526520666200707115259

Abstract

Background: Human immunodeficiency virus (HIV) infection impairs renal function, thereby affecting renal phosphate metabolism.

Objectives: We prospectively estimated the prevalence of phosphate abnormalities (mild, moderate to life-threatening hypophosphataemia, and hyperphosphataemia) before initiating antiretroviral therapy (ART).

Methods: A cross-sectional analysis was performed on 170 consecutive newly diagnosed ARTnaive, HIV-infected patients attending our HIV/AIDS clinics over a period of one year. Fifty (50) screened HIV-negative blood donors were used for comparison (controls). Blood and urine were collected simultaneously for phosphate and creatinine assay to estimate fractional phosphate excretion (FEPi %) and glomerular filtration rate (eGFR).

Results: eGFR showed significant difference between patients’ and controls’ medians (47.89ml/ min/1.73m2 versus 60ml/min/1.73m2, p <0.001); which denotes a moderate chronic kidney disease in the patients. Of the 170 patients, 78 (45.9%) had normal plasma phosphate (0.6-1.4 mmol/L); 85 (50%) had hyperphosphataemia. Grades 1, 2 and 3 hypophosphataemia was observed in 3 (1.8%), 3 (1.8%), and 1(0.5%) patient(s) respectively. None had grade 4 hypophosphataemia. Overall, the patients had significantly higher median of plasma phosphate than the controls, 1.4 mmol/L (IQR: 1.0 – 2.2) versus 1.1 mmol/L (IQR: 0.3 – 1.6), p <0.001, implying hyperphosphataemia in the patients; significantly lower median urine phosphate than the controls, 1.5 mmol/L (IQR: 0.7 -2.1) versus 8.4 mmol/L (IQR: 3.4 – 16), p <0.001), justifying the hyperphosphataemia is from phosphate retention; but a non-significantly lower median FEPi% than the controls, 0.96% (IQR: 0.3 -2.2) versus 1.4% (IQR: 1.2 -1.6), p > 0.05. Predictors of FEPi% were age (Odds ratio, OR 0.9, p = 0.009); weight (OR 2.0, p < 0.001); CD4+ cells count predicted urine phosphate among males (p = 0.029).

Conclusion: HIV infection likely induces renal insufficiency with reduced renal phosphate clearance. Thus, hyperphosphataemia is highly prevalent, and there is mild to moderate hypophosphataemia but its life-threatening form (grade 4) is rare among ART-naive HIV patients.

Keywords: Antiretroviral, human Immunodeficiency Virus, hyperphosphataemia, hypophosphataemia, renal handling of phosphate, eGFR.

Graphical Abstract

[1] 
Klotman, P.E. HIV-associated nephropathy. Kidney Int.,  1999, 56(3), 1161-1176.
[http://dx.doi.org/10.1046/j.1523-1755.1999.00748.x] [PMID: 10469389] 
[2] 
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.
[PMID: 11053484] 
[3] 
Gerntholtz, T.E.; Goetsch, S.J.W.; Katz, I. HIV-related nephropathy: a South African perspective. Kidney Int.,  2006, 69(10), 1885-1891.
[http://dx.doi.org/10.1038/sj.ki.5000351] [PMID: 16625149] 
[4] 
Adedeji, T.A.; Adedeji, N.O.; Adebisi, S.A.; Idowu, A.A.; Fawale, M.B.; Jimoh, K.A. Prevalence and Pattern of Chronic Kidney Disease in Antiretroviral-Naïve Patients with HIV/AIDS. J. Int. Assoc. Provid. AIDS Care,  2015, 14(5), 434-440. sagepub.com/journalsPermissions.nav
[http://dx.doi.org/10.1177/2325957415587570] [PMID: 26013249] 
[5] 
Marotta, C.; Di Gennaro, F.; Pizzol, D.; Madeira, G.; Monno, L.; Saracino, A.; Putoto, G.; Casuccio, A.; Mazzucco, W. The At Risk Child Clinic (ARCC): 3 Years of Health Activities in Support of the Most Vulnerable Children in Beira, Mozambique. Int. J. Environ. Res. Public Health,  2018, 15(7), 1350.
[http://dx.doi.org/10.3390/ijerph15071350] [PMID: 29954117] 
[6] 
Marotta, C.; Giaquinto, C.; Di Gennaro, F.; Chhaganlal, K.D.; Saracino, A.; Moiane, J.; Maringhini, G.; Pizzol, D.; Putoto, G.; Monno, L.; Casuccio, A.; Vitale, F.; Mazzucco, W. Pathways of care for HIV infected children in Beira, Mozambique: pre-post intervention study to assess impact of task shifting. BMC Public Health,  2018, 18(1), 703.
[http://dx.doi.org/10.1186/s12889-018-5646-8] [PMID: 29879951] 
[7] 
Buchacz, K.; Brooks, J.T.; Tong, T.; Moorman, A.C.; Baker, R.K.; Holmberg, S.D.; Greenberg, A. HIV Outpatient Study (HOPS) Investigators. Evaluation of hypophosphataemia in tenofovir disoproxil fumarate (TDF)-exposed and TDF-unexposed HIV-infected out-patients receiving highly active antiretroviral therapy. HIV Med.,  2006, 7(7), 451-456.
[http://dx.doi.org/10.1111/j.1468-1293.2006.00407.x] [PMID: 16925731] 
[8] 
WHOPAR part 4. Efavirenz/Lamivudine/Tenofovir disoproxil fumarate 600mg/300mg/300mg Tablets (Matrix Lab. Ltd) 2011. August 2011  HA466
[9] 
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.
[http://dx.doi.org/10.1053/j.ajkd.2011.01.022] [PMID: 21435764] 
[10] 
Szczech, L.A. Renal dysfunction and tenofovir toxicity in HIV-infected patients. Top. HIV Med.,  2008, 16(4), 122-126.
[PMID: 18838746] 
[11] 
Bringhurst, F.R.; Demay, M.B.; Krane, S.M.; Kronenberg, H.M. Bone and mineral metabolism in health and diseaseHarrison's Principles of Internal Medicine, 16th edn; Kasper, DL.; Fauci, AS.; Longo, DL.; Brunwald, E.; Hauser, SL.; Jameson, JL., Eds.; McGraw-Hill Co., Inc., 2004, pp. 2241-2243.
[12] 
Badiou, S.; De Boever, C.M.; Terrier, N.; Baillat, V.; Cristol, J.P.; Reynes, J. Is tenofovir involved in hypophosphatemia and decrease of tubular phosphate reabsorption in HIV-positive adults? J. Infect.,  2006, 52(5), 335-338.
[http://dx.doi.org/10.1016/j.jinf.2005.07.020] [PMID: 16176835] 
[13] 
Gallant, J.E.; Staszewski, S.; Pozniak, A.L.; DeJesus, E.; Suleiman, J.M.; Miller, M.D.; Coakley, D.F.; Lu, B.; Toole, J.J.; Cheng, A.K. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA,  2004, 292(2), 191-201.
[http://dx.doi.org/10.1001/jama.292.2.191] [PMID: 15249568] 
[14] 
Endres, D.B.; Rude, R.K. Mineral and bone metabolism.Teitz textbook of clinical chemistry, 4th ed; Burtis, C.A.; Ashwood, E.R., Eds.; W. B. Saunders: Philadelphia, 1999, pp. 1905-1908.
[15] 
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.
[http://dx.doi.org/10.1093/ndt/gfh658] [PMID: 15741212] 
[16] 
Norman, J. The results.How to write a paper, 4th ed; Hall, G.M., Ed.; BMJ publishing group: Nottingham, 1994, pp. 19-32.
[17] 
Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Table for Grading the Severity of Adult and Pediatric Adverse Events., http://rcc.tech-res-intl.com/tox_tables.htm 2004.
[18] 
Tietz, N. Clinical Guide to laboratory tests; W. B. Saunders: Philadelphia, 1983, p. 384.
[19] 
Tanganelli, E.; Prencipe, L.; Bassi, D.; Cambiaghi, S.; Murador, E. Enzymic assay of creatinine in serum and urine with creatinine iminohydrolase and glutamate dehydrogenase. Clin. Chem.,  1982, 28(7), 1461-1464.
[http://dx.doi.org/10.1093/clinchem/28.7.1461] [PMID: 7083556] 
[20] 
Flandre, P.; Pugliese, P.; Cuzin, L.; Bagnis, C.I.; Tack, I.; Cabié, A.; Poizot-Martin, I.; Katlama, C.; Brunet-François, C.; Yazdanpanah, Y.; Dellamonica, P. New AIDS Data group. Risk factors of chronic kidney disease in HIV-infected patients. Clin. J. Am. Soc. Nephrol.,  2011, 6(7), 1700-1707.
[http://dx.doi.org/10.2215/CJN.09191010] [PMID: 21566114] 
[21] 
Swanepoel, C.R.; Atta, M.G.; D’Agati, V.D.; Estrella, M.M.; Fogo, A.B.; Naicker, S.; Post, F.A.; Wearne, N.; Winkler, C.A.; Cheung, M.; Wheeler, D.C.; Winkelmayer, W.C.; Wyatt, C.M. Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int.,  2018, 93(3), 545-559.
[http://dx.doi.org/10.1016/j.kint.2017.11.007] [PMID: 29398134] 
[22] 
Obirikorang, C.; Osakunor, D.N.M.; Ntaadu, B.; Adarkwa, O.K. Renal function in Ghanaian HIV-infected patients on highly active antiretroviral therapy: a case-control study. PLoS One,  2014, 9(6), e99469.
[http://dx.doi.org/10.1371/journal.pone.0099469] [PMID: 24921259] 
[23] 
Milburn, J.; Jones, R.; Levy, J.B. Renal effects of novel antiretroviral drugs. Nephrol. Dial. Transplant.,  2017, 32(3), 434-439.
[PMID: 27190354] 
[24] 
Alfano, G.; Cappelli, G.; Fontana, F.; Di Lullo, L.; Di Iorio, B.; Bellasi, A.; Guaraldi, G. Kidney Disease in HIV Infection. J. Clin. Med.,  2019, 8(8), 1254.
[http://dx.doi.org/10.3390/jcm8081254] [PMID: 31430930] 
[25] 
Fabian, J.; Naicker, S. HIV and the Kidney. Tropical Journal of Nephrology.,  2008, 3(1), 7-22.
[26] 
Reynes, J.; Peyriere, H.; Merle de Boever, C. Renal tubular injury and severe hypophosphataemia (Fanconi Syndrome) associated with tenofovir therapy. 10th Conference on Retroviruses and Opportunistic infection, Boston, USA 2003.
[27] 
Verhelst, D.; Monge, M.; Meynard, J.L.; Fouqueray, B.; Mougenot, B.; Girard, P.M.; Ronco, P.; Rossert, J. Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am. J. Kidney Dis.,  2002, 40(6), 1331-1333.
[http://dx.doi.org/10.1053/ajkd.2002.36924] [PMID: 12460055] 
[28] 
Créput, C.; Gonzalez-Canali, G.; Hill, G.; Piketty, C.; Kazatchkine, M.; Nochy, D. Renal lesions in HIV-1-positive patient treated with tenofovir. AIDS,  2003, 17(6), 935-937.
[http://dx.doi.org/10.1097/00002030-200304110-00026] [PMID: 12660548] 
[29] 
Block, G.A.; Hulbert-Shearon, T.E.; Levin, N.W.; Port, F.K. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am. J. Kidney Dis.,  1998, 31(4), 607-617.
[http://dx.doi.org/10.1053/ajkd.1998.v31.pm9531176] [PMID: 9531176] 
[30] 
Sampaio, M.S.; Molnar, M.Z.; Kovesdy, C.P.; Mehrotra, R.; Mucsi, I.; Sim, J.J.; Krishnan, M.; Nissenson, A.R.; Kalantar-Zadeh, K. Association of pretransplant serum phosphorus with posttransplant outcomes. Clin. J. Am. Soc. Nephrol.,  2011, 6(11), 2712-2721.
[http://dx.doi.org/10.2215/CJN.06190611] [PMID: 21959597] 
[31] 
Block, G.A.; Klassen, P.S.; Lazarus, J.M.; Ofsthun, N.; Lowrie, 
                e.g.
              ; Chertow, G.M. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J. Am. Soc. Nephrol.,  2004, 15(8), 2208-2218.
[http://dx.doi.org/10.1097/01.ASN.0000133041.27682.A2] [PMID: 15284307] 
[32] 
Noordzij M.; Grootendorst D.C.; Beetz I.; Sijpkens Y.W.; van Manen J.G.; Boeschoten E.W.; Huisman R.M.; Krediet R.T.; Dekker F.W. Group tPs: High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients. Nephrol. Dial. Transplant.,  2007, 22, 2909-2916.
[http://dx.doi.org/10.1093/ndt/gfm286] 
[33] 
Kuro-O, M. A phosphate-centric paradigm for pathophysiology and therapy of chronic kidney disease. Kidney Int Suppl (2011),  2013, 3(5), 420-426.
[http://dx.doi.org/10.1038/kisup.2013.88] [PMID: 25019024] 
[34] 
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.
[http://dx.doi.org/10.1038/ki.1993.189] [PMID: 8315949] 
[35] 
Bódi, I.; Abraham, A.A.; Kimmel, P.L. Apoptosis in human immunodeficiency virus-associated nephropathy. Am. J. Kidney Dis.,  1995, 26(2), 286-291.
[http://dx.doi.org/10.1016/0272-6386(95)90648-7] [PMID: 7645532] 
[36] 
Marras, D.; Bruggeman, L.A.; Gao, F.; Tanji, N.; Mansukhani, M.M.; Cara, A.; Ross, M.D.; Gusella, G.L.; Benson, G.; D’Agati, V.D.; Hahn, B.H.; Klotman, M.E.; Klotman, P.E. Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy. Nat. Med.,  2002, 8(5), 522-526.
[http://dx.doi.org/10.1038/nm0502-522] [PMID: 11984599] 
[37] 
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.
[http://dx.doi.org/10.1056/NEJM200106283442604] [PMID: 11430327] 
[38] 
Endres, D.B.; Rude, R.K. Mineral and bone metabolism.Teitz textbook of clinical chemistry; Burtis, C.A.; Ashwood, E.R., Eds.; W. B. Saunders: Philadelphia, 1999, pp. 1905-1908.
[39] 
Gilead Sciences Inc. Background Package for NDA 21-356: VIREAD (tenofovir disoproxil fumarate. 
[40] 
Crook, M.A. Calcium, Phosphate, and Magnesium.Clinical chemistry and metabolic medicine; Holder Arnold: London, 2006, p. 215.
[41] 
Walmsley, R.N.; Guerin, M.D. Renal Disease.Disorders of fluid and electrolyte balance; John Wright: Bristol, 1984, pp. 153-160.
[42] 
Kovesdy, C.P.; Kalantar-Zadeh, K. Bone and mineral disorders in pre-dialysis CKD. Int. Urol. Nephrol.,  2008, 40(2), 427-440.
[http://dx.doi.org/10.1007/s11255-008-9346-7] [PMID: 18368510] 
[43] 
Taniguchi, M. CKD-MBD (Chronic Kidney Disease-Mineral and Bone Disorder). The impact of CKD-MBD on mortality. Clin. Calcium,  2010, 20(7), 1078-1087.
[PMID: 20585187] 
[44] 
Rosner, M.H.; Bolton, W.K. Core curriculum in nephrology. Am. J. Kidney Dis.,  2006, 47(1), 174-183.
[http://dx.doi.org/10.1053/j.ajkd.2005.08.038] [PMID: 16377400] 
[45] 
Keating, F.R., Jr; Jones, J.D.; Elveback, L.R.; Randall, R.V. The relation of age and sex to distribution of values in healthy adults of serum calcium, inorganic phosphorus, magnesium, alkaline phosphatase, total proteins, albumin, and blood urea. J. Lab. Clin. Med.,  1969, 73(5), 825-834.
[PMID: 5779266] 
[46] 
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.
[http://dx.doi.org/10.1056/NEJMc0800696] [PMID: 18716307] 
[47] 
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.
[PMID: 15735448] 
[48] 
Berndt, T.; Kumar, R. Novel mechanisms in the regulation of phosphorus homeostasis. Physiology (Bethesda),  2009, 24, 17-25.
[http://dx.doi.org/10.1152/physiol.00034.2008] [PMID: 19196648] 
[49] 
Jüppner, H. Phosphate and FGF-23. Kidney Int. Suppl.,  2011, 121(121), S24-S27.
[http://dx.doi.org/10.1038/ki.2011.27] [PMID: 21346724] 

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DOI https://dx.doi.org/10.2174/1871526520666200707115259	Print ISSN 1871-5265
Publisher Name Bentham Science Publisher	Online ISSN 2212-3989

Infectious Disorders - Drug Targets

Renal Phosphate Handling in Antiretroviral-naive HIV-Infected Patients

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