Renal effect of atazanavir-ritonavir in pregnant albino rats

Elias Adikwu, Ben E Ehigiator

Abstract


Background: Pregnancy could be associated with renal physiologic changes; hence the use of atazanvair/ritonavir (ATV/r) in pregnant women with human immunodeficiency virus (HIV) could be of safety concern due to its nehprotoxic potential.

Objective: The present study was aimed at assessing the renal profile of atazanavir/ritonavir (ATV/r) in pregnant albino rats.

Methods: Thirty six pregnant albino rats were randomized into six groups (A-E) of n=6. Rats in groups A and B were treated with water and normal saline as placebo and solvent control respectively. Rats in groups C-F were orally treated daily with 4.28/1.43, 8.57/2.86, 17.1/5.7 and 34/11.4 mg/kg of ATV/r for 16 days. Rats were weighed, sacrificed and blood was collected and serum extracted. The serum was evaluated for creatinine (Cr), urea (U), uric acid (UA), total protein (TP), albumin (Ab), potassium (K+), sodium (Na+), chloride ( Cl-) and bicarbonate (HCO3 -). Kidneys were harvested, weighed and evaluated for superoxide dismutase (SOD), catalase (CAT) glutathione (GSH), glutathione peroxidase (GPX) and malondialdehyde (MDA) levels. Kidneys were also evaluated for histological damage.

Results: ATV/r-treated groups did not show significant (p> 0.05) changes in the body weight, kidney weight and serum electrolytes, however; serum levels of Cr, U, UA were significantly (p< 0.05) increased whereas Ab and TP were significantly (p< 0.05) decreased in a dose-dependent manner. Kidney SOD, CAT, GSH and GPX levels were significantly (p< 0.05) decreased whereas MDA levels were significantly (p< 0.05) increased in a dose dependent manner in ATV/r-treated rats. Varying degrees of histological damage were observed in the kidneys of ATV/r treated rats.

Conclusion: This study observed dose-dependent nephrotoxic effects in ATV/r-treated pregnant albino rats.

Keywords: Atazanavir/ritonavir; Kidney, Toxicity, Pregnant; Rats


References


Aebi H (1984). Catalase in vitro. in Method in Enzymology, S. P. Colowick and N. O. Kaplane, Eds., Academic Press, New York, NY, USA.

Allen PJ (2012). Creatine Metabolism and Psychiatric Disorders: Does Creatine Supplementation Have Therapeutic Value? Neurosci. Biobehav. Rev. 36:1442-1462.

Ambwani SR, Desai MK, Girdhar AO, Shah UH, Mathur AK (1999). Role of serum electrolytes (Magnesium and Calcium) in Essential Hypertension. Indian J. Cardiol. 1: 30-32.

Ansari MA, Joshi G, Huang Q, Opii. W.O, Abdul HM, Sultana R, Butterfield DA (2006). In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer's disease and other oxidative stress-related neurodegenerative disorders. Free Rad. Biol. Med. 41:1694–1703.

Armstrong LE, Hubbard RW, Szlyk PC, Matthew WT, and Sils IV, (1985). Voluntary dehydration and electrolyte losses during Prolonged Exercise in the Heat. Aviation, Space Environ. Med. 56:765-770.

Atta MG, Deray G, and Lucas GM (2008). Antiretroviral nephrotoxicities. Semin. Nephrol. 28:563–575.

Brenner BM, Rector FC. The kidney. 6th ed. Philadelphia, PA: W. B. Saunders Company; 1999.

Brouns F (1992). Rationale for upper limits of electrolyte replacement during exercise. Int. J. Sports Nutr. 2:229-38.

Buege JA and Aust SD, (1978). Microsomal lipid peroxidation. Methods Enzymol. 52: 302-310.

Burdge DR, Money DM, Forbes JC,Walmsley SL, Smaill FM, BoucherM, Samson LM, Steben M (2003). Canadian consensus guidelines for the management of pregnancy, labor and delivery and for post-partum care in HIV-positive women and their offspring (summary of 2002 guidelines). CMAJ 168:1671–4.

Chan-Tack KM, Truffa MM, Struble KA, Birkrant DM (2007). Atazanavir-associated nephrolithiasis: cases from the US Food and Drug Administration’s Adverse Event Reporting System. AIDS. 21:1215–1218.

Cihlar T, Birkus G, Greenwalt DE, Hitchcock MJ (2002). Tenofovir exhibits low cytotoxicity in various human cell types: Comparison with other nucleoside reverse transcriptase inhibitors. Antiviral Res. 54:37-45.

Cihlar T, Lin DC, Pritchard JB, Fuller MD, Mendel DB, Sweet DH (1999). The antiviral nucleotide analogs cidofovir and adefovir dipivoxil are novel substrates for human and rat renal organic anion transporter 1. Mol. Pharmacol. 56:570-580.

Clark R (2005). Sex Differences in antiretroviral therapy-associated intolerance and adverse events. Drug Safety. 28: 1075-1083.

Corbett JV. Laboratory tests and diagnostic procedures with nursing diagnoses. 7th Ed (2008).; pp. 90–107.

Davison JM, Dunlop W. (1980). Renal hemodynamics and tubular function normal human pregnancy. Kidney Int. 18:152–161

Dawes M, Chowienczyk PJ. (2001). Drugs in pregnancy. Pharmacokinetics in pregnancy. Best Pract. Res. Clin. Obstet. Gynaecol. 15:819-26.

Duryea E, Nicholson F, Cooper S, Roberts S, Rogers V, McIntire D, Sheffield J, Stewart R (2015) The Use of Protease Inhibitors in Pregnancy: Maternal and Fetal Considerations. Infect. Dis. Obst. Gynaecol. Article ID 563727.

Gowda S, Desai PB, Kulkarni SS, Hull VV, Math AAK, Vernekar SN (2010). Markers of renal function tests. N. Am. J. Med. Sci. 2:170-173

Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML and Zelmanovitz T (2005) Diabetic Nephropathy: Diagnosis, Prevention, and Treatment. Diabetes Care. 28, 164-176

Grünfeld JP, Pertuiset N (1987). Acute renal failure in pregnancy. Am. J. Kidney Dis. 9:359.

Guiard-Schmid JB, Poirier JM, Bonnard P, Meynard JL, Slama L, Lukiana T, Jaillon P, Pialoux G et al (2005) Proton pump inhibitors do not reduce atazanavir concentrations in HIV-infected patients treated with ritonavir-boosted atazanavir. AIDS. 19:1937–8.

Hamada Y, Nishijima T, Watanabe K, Komatsu H, Tsukada K (2012). High incidence of renal stones among HIV-infected patients on ritonavir-boosted atazanavir than in those receiving other protease inhibitor-containing antiretroviral therapy. Clin. Infect. Dis., 55:1262–1269

Hara M, Suganuma A, Yanagisawa N, Imamura A, Hishima T and Ando M Clin (2015). Atazanavir nephrotoxicity. Kidney J. 8: 137–142

Ho ES, Lin DC, Mendel DB, Cihlar T (2000). Cytotoxicity of antiviral nucleotides adefovir dipivoxil and cidofovir is induced by the expression of human renal organic anion transporter 1. J. Am. Soc. Nephrol. 11:383-393

Izzedine H, Harris M and Mark A (2009). The nephrotoxic effects of HAART. Nat. Rev. Nephrol. 5:563–573

Kalyesubula R and Perazella MA (2011). Nephrotoxicity of HAART. AIDS Research. Article ID 562790.

Kellum JA, Lameire N, Aspelin P, MacLeod AM, Barsoum RS, Mehta RL, Murray PT, Naicker S. Opal SM, Schaefer F, Schetz M, Uchino S. (2012) KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int. Suppl. 2:1-138

Khan A, Tania M, Zhang D, Chen HC (2010) Antioxidant Enzymes and Cancer. Chin. J. Cancer Res. 22: 87-92.

Krane NK (1988). Acute renal failure in pregnancy. Arch. Intern. Med. 148:2347.

Lang PA, Jones CC (1964) Acute Renal Failure Precipitated by Quinine Sulfate in Early Pregnancy JAMA. 188:464-466.

Leeuwenburgh C and Heinecke W (2001) Oxidative stress and antioxidants in exercise. Curr. Med. Chem. 8:829-838

Lüllmann H, Lüllmann-Rauch R, Wassermann O (1975). Drug-induced phospholipidoses. II. Tissue distribution of the amphiphilic drug chlorphentermine. CRC Crit. Rev. Toxicol. 4:185-218.

Odutayo A, Hladunewich M (2012) Obstetric nephrology: renal hemodynamic and metabolic physiology in normal pregnancy. Clin. J. Am. Soc. Nephrol. 7:2073–2080

Okonkwo OP, Bello AC and Ogbe JR (2013). Evaluation of changes in renal functions of pregnant women attending antenatal clinic in Vom Plateau State, North-Central Nigeria. Arch. Appl. Sci. Res. 5:111-116.

Omotayo EO, Gurtu S, Sulaiman SA, Wahab MS, Sirajudeen KN, and Salleh MS, (2010) Hypoglycemic and antioxidant effects of honey supplementation in streptozotocin-induced diabetic rats, Int. J. Vit. Nutr. Res. 80:74–82,

Pagana KD. St. Louis, MO, Mosby, Inc; (1998). Mosby's manual of diagnostic and laboratory tests.

Perazella MA. (2010). Tenofovir-induced kidney disease: an acquired renal tubular mitochondriopathy, Kidney Int. 78:1060–1063,

Plummer DT (1971). An Introduction to Practical Biochemistry. McGraw-Hill, London 2nd edition

Rockwood N, Mandalia S, Bower M, Gazzard B, Nelson M (2011) Ritonavir-boosted atazanavir exposure is associated with an increased rate of renal stones compared with efavirenz, ritonavir-boosted lopinavir and ritonavir-boosted darunavir. AIDS. 25: 1671–1673

Rotruck JT, Rope AL, Ganther HF, Swason AB. (1973) Selenium: biochemical role as a component of glutathione peroxidase. Science. 179: 588–90.

Sanders GTB, Pasman AJ and Hoek FJ (1980) Determination of uric acid with uricase and peroxidase. Clin. Chem. Acta. 101: 299-303,

Saumoy M, Vidal F, Peraire J, Sauleda, S., Vea, A. M., Viladés, C., Ribera, E., and Richart, C (2004). Proximal tubular kidney damage and tenofovir: A role for mitochondrial toxicity? AIDS. 18:1741-1742

Sedlak J. and Lindsay RH.(1968). Estimation of Total, Protein-Bound, and Nonprotein Sulfhydryl Groups in Tissue with Ellman’s Reagent. Anal. Biochem, 25: 1192-1205

Sinha, K.A., (1972). Colorimetric assay of catalase. Anal. Biochem. 47: 389-394

Sun, M. and Zigma S (1978).An ImprovedSpectrophotometer Assay of Superoxide Dismutase Based On Epinephrine Antioxidation. Anal. Biochem. 90: 81-89

Tietz NW, Pruden EL, Siggaard-Andersen O (1994). In: Tietz textbook of Clinical Chemistry (Burtis C.A. and Ashwood E.R. Ed.) W.B. Saunders Company London. pp. 1395-1406

van der Velde M, Matsushita K, Coresh J, Astor BC, Woodward M, Levey A, de Jong P, Gansevoort RT (2011). Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney Int. 79:1341–52.

van Hook JW. (2014). Acute kidney injury during pregnancy. Clin. Obstet. Gynecol. 57:851-61.

van Schalkwyk J, Alimenti A, Khoo D, Maan E, Forbes J, Burdge D, Gilgoff S, Money D. (2008). Serious toxicity associated with continuous nevirapine-based HAART in pregnancy. BJOG, 115:1297–1302

Vancini RL, Lira CAB, Guedes Júnior DP, Silva AC, Nouailhetas VLA. (2005). Influência do exercício sobre a produção de radicais livres. Rev. Bras. Ativ. Fis. Saude. 10: 47-58.

Wilber C.G. and Gilchrist R.D. (1965). Organ Weight: Body Weight Ratios in the Mongolian Gerbil, Meriones Unguiculatus. Chesapeake Science, 6:109-114

Young DS (1987). Implementation of SI Units for Clinical Laboratory Data. Ann. Inter. Med. 106:114–6.

Youssef H, Zidan. A (2016). Histopathological and Biochemical Effects of Acute and Chronic Tramadol Drug Toxicity on Liver, Kidney and Testicular Function in Adult Male Albino Rats. J. Med. Toxicol. Forensic Med. 1: DOI:10.21767/2471-9641.10007


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