American Journal of Therapeutics 23, e558–e560 (2016)
Fanconi Syndrome and Antiretrovirals: It Is Never Too Late Faraz Khan Luni, MD,* Abdur Rahman Khan, MD, Rohini Prashar, MD, Sandeep Vetteth, MD, and Joan M. Duggan, MD
Antiretroviral medications such as tenofovir have been associated with Fanconi syndrome (FS) usually identified within the first 1–29 months after exposure to the medication. We present a case of life-threatening FS which developed in a 37-year-old woman with HIV after 8 years of asymptomatic tenofovir use. The patient was diagnosed with HIV in 1996 at 20 years of age, hepatitis C 10 years later, and Staphylococcus aureus sepsis with secondary osteomyelitis of the spine 3 years before admission for FS. She developed nausea, vomiting, diarrhea, and generalized weakness over a 2-week time period and presented to the hospital. In the emergency department, her serum potassium was 1.5 mEq/L, bicarbonate was 12 mEq/L, chloride was 111 mEq/L, phosphorus was 1.8 mg/dL, and creatinine was 1.95 mg/dL (baseline, 1.4). Arterial blood gas revealed a non–anion gap (hyperchloremic) metabolic acidosis. Type 2 renal tubular acidosis induced by antiretroviral therapy (ART) was suspected and the ART was discontinued with resolution of the renal abnormalities within 7 days. A non–tenofovir-containing ART regimen consisting of lamivudine/abacavir and efavirenz was begun, and over the next 8 months, the patient was without recurrence of the FS. This case report demonstrates the acute development of FS after prolonged exposure to tenofovir without exposure to additional nephrotoxins such as nonsteroidal medications or aminoglycosides. Tenofovir can cause FS at any time and should be considered in any patient presenting with renal tubular acidosis type 2 while on tenofovir regardless of the duration of drug exposure. Keywords: Fanconi syndrome, tenofovir, antiretroviral medication, HIV
BACKGROUND Tenofovir is a potent nucleotide analog reversetranscriptase inhibitor used in the treatment of HIV and hepatitis B virus.1 The Department of Health and Human Services guidelines list tenofovir as one of the preferred analog reverse-transcriptase inhibitor backbones for antiretroviral treatment regimens for antiretroviral-naive adults and adolescents.2 Tenofovir
Department of Medicine, University of Toledo Health Science Campus, Toledo, OH. The authors have no conflicts of interest to declare. F. K. Luni, A. R. Khan, S. Vetteth, R. Prashar, and J. M. Duggan all participated in the care of this patient, the diagnostic workup, data acquisition and interpretation, and article preparation. *Address for correspondence: Department of Medicine, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH 43614. E-mail: [email protected]
is relatively a safe drug with 455,392 person-years of cumulative experience in Europe and the United States up to the end of 2007, with the data indicating a favorable side effect profile.3 There have been multiple case reports of Fanconi syndrome (FS) in the literature with the time lapse between initiation of tenofovir and renal abnormalities ranging from 1 to 29 months.4 We present a case of an HIV-infected woman who had received tenofovir-containing antiretroviral therapy (ART) for almost a decade after which she developed FS.
CASE PRESENTATION We present the case of a 37-year-old woman with HIV, Hepatitis C, and chronic osteomyelitis on suppression antibiotic therapy with doxycycline who developed Fanconi syndrome due to tenofovir after 8 years of medication usage. The patient was diagnosed with HIV in 1996 at 20 years of age and hepatitis C 10 years later. Her initial ART was zidovudine/lamivudine and
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www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Fanconi Syndrome: Review
nelfinavir, which she received from 1996 to 2006, at which time, she was changed to efavirenz and tenofovir/emtricitabine. She maintained an undetectable viral load and CD counts .350 cells/mm3 over 18 years except for 3 discrete intervals of time each lasting up to 1 year when she independently discontinued ART due to depression or loss of insurance. Over this 18-year-period, she did not develop a K103 or M184V mutation despite occasional nonadherence. Three years before admission, she developed Staphyloccus aureus with bacteremia and multiorgan system dysfunction, including severe hypotension, respiratory failure requiring mechanical ventilation, and acute renal failure with the maximum creatinine of 5.4 mg/dL (baseline, 0.7–1.01). The source of the bacteremia was a complicated skin and soft tissue abscess. Within 3 months, her renal function returned to normal, and she resumed her efavirenz/tenofovir/emtricitabine in a combination formulation without renal adjustment. She presented 3 years later with nausea and vomiting for 2 weeks and diarrhea and severe generalized weakness for 2 days. On admission, her serum potassium was 1.5 mEq/L, bicarbonate 12 mEq/L, chloride 111 mEq/L, phosphorus 1.8 mg/dL, and creatinine 1.95 mg/dL (baseline, 0.9). Toxicology screen was negative except for prescribed medications. Arterial blood gas revealed non–anion gap (hyperchloremic) metabolic acidosis with pH of 7.05: urine anion gap was 23, glucose in urine was 250 mg/dL, and urinary pH was 5.5. Generalized aminoaciduria and phosphaturia were present on further examination. Type 2 renal tubular acidosis (RTA) induced by tenofovir was suspected. Supportive treatment was initiated with a bicarbonate drip, electrolytes were replaced aggressively and her ART was held. Her symptoms resolved with supportive therapy, and she was started on raltegravir and darunavir/norvir till HLA B5701 antigen testing was confirmed as negative. She was changed to lamivudine/abacavir and efavirenz and has maintained an undetectable viral load without evidence of Fanconi syndrome for over 6 months.
CONCLUSIONS Fanconi syndrome was initially described by Lignac in 1924 and with further refinement of the syndrome by Fanconi in 1936.5 FS is a generalized transport defect in the proximal tubule6 of kidneys resulting in variable loss of phosphate, amino acids, glucose, calcium, uric acids, and bicarbonate.5,6 There are various causes of FS with medications, such as ifosfamide, tenofovir, acetazolamide, topiramate, and aminoglycosides, among the drugs known to cause FS.5 Tenofovir is a potent NRTI.1 The other nephrotoxic drugs in this class are adefovir that inhibits mitochondrial www.americantherapeutics.com
e559
DNA (mtDNA) replication resulting in depletion of mtDNA from proximal tubular cells7 and cidofovir.8 Renal uptake and accumulation of these drugs in the proximal convoluted tubules by human organic anion transporter 19 and decreased luminal efflux by functional involvement of multidrug resistance–associated protein 4 (MRP4/ABCC4)10 results in intracellular accumulation of these drugs. Increased levels of these drugs can cause nephrotoxicity due to transporter defects, mitochondrial injury, and proximal tubular toxicity.11 Low-dose tenofovir in macaques did not cause any adverse effects, whereas higher doses for prolonged periods caused Fanconi-like syndrome, which was reversed or alleviated by complete withdrawal or decrease of the dose of tenofovir.12 In an additional studies conducted on rats, rhesus monkeys, and woodchucks, tenofovir did not affect mtDNA content or the levels of mitochondrial enzymes in tenofovir-treated animals and no liver, muscle, or renal microscopic abnormalities were observed.13 Tenofovir has a favorable safety profile in human trials with 1 large clinical trial, which showing no Fanconi syndrome or discontinuation from study due to tenofovir-related renal abnormalities.14 Data from the GS 902 and 903 studies of tenofovir indicated that ,1% of patients discontinued tenofovir treatment due to renal events.15 Fanconi syndrome was not listed as the cause of renal toxicity in these studies, and FS is considered a rare side effect. Despite its rarity, FS in associated with tenofovir has been well documented in various case series and reviews of literature. Zimmermann et al16 in his case series and review of the literature described 27 patients who developed tenofovir-associated acute renal failure with the mean duration of tenofovir therapy being 11 months (range, 1–29 months). Our patient had first received tenofovir in 2006 and had consistently been on a tenofovir-containing regimen for approximately 8 years before the development of FS. This has important clinical implications as FS can occur at any time during the course of treatment and needs to be considered in the differential diagnosis of any patient receiving tenofovir who develops proximal RTA irrespective of the duration of treatment. This late presentation could be from interaction of tenofovir with other medications. Tenofovir when combined with didanosine or a protease inhibitor has been associated with cumulative effects,17,18 and it is suspected that tenofovir with PIs can interact with renal organic anion transporters, leading to nephrotoxic tubular concentrations of tenofovir. Our patient was not on a combination containing a protease inhibitor, so this is not a possibility. Our patient was also on doxycycline for chronic suppression of osteomyelitis. Aminoglycosides have been American Journal of Therapeutics (2016) 23(2)
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e560
associated with FS, which is dependent on the duration of treatment and cumulative dose, but doxycycline has not been implicated as a causative agent.6 Also, it is highly unlikely that doxycycline was the offending agent as the patient recovered after discontinuing the tenofovir while the doxycycline was never discontinued. Complete or partial recovery is usually seen once tenofovir is discontinued11 as was seen in our patient. In summary, FS is a serious renal toxicity associated with the use of tenofovir, and there may be various factors that may trigger FS. This case illustrates tenofovir-associated Fanconi syndrome developing after prolonged exposure at any time. FS can occur at any time during the course of treatment and needs to be considered in the differential diagnosis of any patient receiving tenofovir who develops proximal RTA irrespective of the duration of treatment.
REFERENCES 1. Gallant JE, Deresinski S. Tenofovir disoproxil fumarate. Clin Infect Dis. 2003;37:944–950. 2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescent GL.pdf. Accessed May 27, 2014. 3. Nelson MR, Katlama C, Montaner JS, et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS. 2007;21:1273– 1281. 4. Malik A, Abraham P, Malik N. Acute renal failure and Fanconi syndrome in an AIDS patient on tenofovir treatment—case report and review of literature. J Infect. 2005; 51:E61–E65. 5. Izzedine H, Launay-Vacher V, Isnard-Bagnis C, et al. Drug-induced Fanconi’s syndrome. Am J Kidney Dis. 2003;41:292–309. 6. Ghiculescu RA, Kubler PA. Aminoglycoside-associated Fanconi syndrome. Am J Kidney Dis. 2006;48:e89–e93.
American Journal of Therapeutics (2016) 23(2)
Luni et al 7. Tanji N, Tanji K, Kambham N, et al. Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion. Hum Pathol. 2001;32:734–740. 8. Meier P, Dautheville-Guibal S, Ronco PM, et al. Cidofovirinduced end-stage renal failure. Nephrol Dial Transplant. 2002;17:148–149. 9. Cihlar T, Lin DC, Pritchard JB, et al. The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1. Mol Pharmacol. 1999;56:570–580. 10. Imaoka T, Kusuhara H, Adachi M, et al. Functional involvement of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir. Mol Pharmacol. 2007;71: 619–627. 11. Jao J, Wyatt CM. Antiretroviral medications: adverse effects on the kidney. Adv Chronic Kidney Dis. 2010;17:72–82. 12. Van Rompay KK, Brignolo LL, Meyer DJ, et al. Biological effects of short-term or prolonged administration of 9-[2(phosphonomethoxy) propyl] adenine (tenofovir) to newborn and infant rhesus macaques. Antimicrob Agents Chemother. 2004;48:1469–1487. 13. Biesecker G, Karimi S, Desjardins J, et al. Evaluation of mitochondrial DNA content and enzyme levels in tenofovir DF-treated rats, rhesus monkeys and woodchucks. Antiviral Res. 2003;58:217–225. 14. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292:191–201. 15. Winiarczyk M, Sikora A, Mikula T, et al. Nephrotoxicity of Tenofovir true or myth? HIV AIDS Rev. 2009;8:17–20. 16. Zimmermann AE, Pizzoferrato T, Bedford J, et al. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis. 2006; 42:283–290. 17. Irizarry-Alvarado JM, Dwyer JP, Brumble LM, et al. Proximal tubular dysfunction associated with tenofovir and didanosine causing Fanconi syndrome and diabetes insipidus: a report of 3 cases. AIDS Read. 2009;19:114–121. 18. Rollot F, Nazal EM, Chauvelot-Moachon L, et al. Tenofovirrelated Fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome: the role of lopinavir-ritonavir-didanosine. Clin Infect Dis. 2003;37:e174–e176.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Fanconi Syndrome and Antiretrovirals: It Is Never Too Late Faraz Khan Luni, MD,* Abdur Rahman Khan, MD, Rohini Prashar, MD, Sandeep Vetteth, MD, and Joan M. Duggan, MD
Antiretroviral medications such as tenofovir have been associated with Fanconi syndrome (FS) usually identified within the first 1–29 months after exposure to the medication. We present a case of life-threatening FS which developed in a 37-year-old woman with HIV after 8 years of asymptomatic tenofovir use. The patient was diagnosed with HIV in 1996 at 20 years of age, hepatitis C 10 years later, and Staphylococcus aureus sepsis with secondary osteomyelitis of the spine 3 years before admission for FS. She developed nausea, vomiting, diarrhea, and generalized weakness over a 2-week time period and presented to the hospital. In the emergency department, her serum potassium was 1.5 mEq/L, bicarbonate was 12 mEq/L, chloride was 111 mEq/L, phosphorus was 1.8 mg/dL, and creatinine was 1.95 mg/dL (baseline, 1.4). Arterial blood gas revealed a non–anion gap (hyperchloremic) metabolic acidosis. Type 2 renal tubular acidosis induced by antiretroviral therapy (ART) was suspected and the ART was discontinued with resolution of the renal abnormalities within 7 days. A non–tenofovir-containing ART regimen consisting of lamivudine/abacavir and efavirenz was begun, and over the next 8 months, the patient was without recurrence of the FS. This case report demonstrates the acute development of FS after prolonged exposure to tenofovir without exposure to additional nephrotoxins such as nonsteroidal medications or aminoglycosides. Tenofovir can cause FS at any time and should be considered in any patient presenting with renal tubular acidosis type 2 while on tenofovir regardless of the duration of drug exposure. Keywords: Fanconi syndrome, tenofovir, antiretroviral medication, HIV
BACKGROUND Tenofovir is a potent nucleotide analog reversetranscriptase inhibitor used in the treatment of HIV and hepatitis B virus.1 The Department of Health and Human Services guidelines list tenofovir as one of the preferred analog reverse-transcriptase inhibitor backbones for antiretroviral treatment regimens for antiretroviral-naive adults and adolescents.2 Tenofovir
Department of Medicine, University of Toledo Health Science Campus, Toledo, OH. The authors have no conflicts of interest to declare. F. K. Luni, A. R. Khan, S. Vetteth, R. Prashar, and J. M. Duggan all participated in the care of this patient, the diagnostic workup, data acquisition and interpretation, and article preparation. *Address for correspondence: Department of Medicine, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH 43614. E-mail: [email protected]
is relatively a safe drug with 455,392 person-years of cumulative experience in Europe and the United States up to the end of 2007, with the data indicating a favorable side effect profile.3 There have been multiple case reports of Fanconi syndrome (FS) in the literature with the time lapse between initiation of tenofovir and renal abnormalities ranging from 1 to 29 months.4 We present a case of an HIV-infected woman who had received tenofovir-containing antiretroviral therapy (ART) for almost a decade after which she developed FS.
CASE PRESENTATION We present the case of a 37-year-old woman with HIV, Hepatitis C, and chronic osteomyelitis on suppression antibiotic therapy with doxycycline who developed Fanconi syndrome due to tenofovir after 8 years of medication usage. The patient was diagnosed with HIV in 1996 at 20 years of age and hepatitis C 10 years later. Her initial ART was zidovudine/lamivudine and
1075–2765 Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Fanconi Syndrome: Review
nelfinavir, which she received from 1996 to 2006, at which time, she was changed to efavirenz and tenofovir/emtricitabine. She maintained an undetectable viral load and CD counts .350 cells/mm3 over 18 years except for 3 discrete intervals of time each lasting up to 1 year when she independently discontinued ART due to depression or loss of insurance. Over this 18-year-period, she did not develop a K103 or M184V mutation despite occasional nonadherence. Three years before admission, she developed Staphyloccus aureus with bacteremia and multiorgan system dysfunction, including severe hypotension, respiratory failure requiring mechanical ventilation, and acute renal failure with the maximum creatinine of 5.4 mg/dL (baseline, 0.7–1.01). The source of the bacteremia was a complicated skin and soft tissue abscess. Within 3 months, her renal function returned to normal, and she resumed her efavirenz/tenofovir/emtricitabine in a combination formulation without renal adjustment. She presented 3 years later with nausea and vomiting for 2 weeks and diarrhea and severe generalized weakness for 2 days. On admission, her serum potassium was 1.5 mEq/L, bicarbonate 12 mEq/L, chloride 111 mEq/L, phosphorus 1.8 mg/dL, and creatinine 1.95 mg/dL (baseline, 0.9). Toxicology screen was negative except for prescribed medications. Arterial blood gas revealed non–anion gap (hyperchloremic) metabolic acidosis with pH of 7.05: urine anion gap was 23, glucose in urine was 250 mg/dL, and urinary pH was 5.5. Generalized aminoaciduria and phosphaturia were present on further examination. Type 2 renal tubular acidosis (RTA) induced by tenofovir was suspected. Supportive treatment was initiated with a bicarbonate drip, electrolytes were replaced aggressively and her ART was held. Her symptoms resolved with supportive therapy, and she was started on raltegravir and darunavir/norvir till HLA B5701 antigen testing was confirmed as negative. She was changed to lamivudine/abacavir and efavirenz and has maintained an undetectable viral load without evidence of Fanconi syndrome for over 6 months.
CONCLUSIONS Fanconi syndrome was initially described by Lignac in 1924 and with further refinement of the syndrome by Fanconi in 1936.5 FS is a generalized transport defect in the proximal tubule6 of kidneys resulting in variable loss of phosphate, amino acids, glucose, calcium, uric acids, and bicarbonate.5,6 There are various causes of FS with medications, such as ifosfamide, tenofovir, acetazolamide, topiramate, and aminoglycosides, among the drugs known to cause FS.5 Tenofovir is a potent NRTI.1 The other nephrotoxic drugs in this class are adefovir that inhibits mitochondrial www.americantherapeutics.com
e559
DNA (mtDNA) replication resulting in depletion of mtDNA from proximal tubular cells7 and cidofovir.8 Renal uptake and accumulation of these drugs in the proximal convoluted tubules by human organic anion transporter 19 and decreased luminal efflux by functional involvement of multidrug resistance–associated protein 4 (MRP4/ABCC4)10 results in intracellular accumulation of these drugs. Increased levels of these drugs can cause nephrotoxicity due to transporter defects, mitochondrial injury, and proximal tubular toxicity.11 Low-dose tenofovir in macaques did not cause any adverse effects, whereas higher doses for prolonged periods caused Fanconi-like syndrome, which was reversed or alleviated by complete withdrawal or decrease of the dose of tenofovir.12 In an additional studies conducted on rats, rhesus monkeys, and woodchucks, tenofovir did not affect mtDNA content or the levels of mitochondrial enzymes in tenofovir-treated animals and no liver, muscle, or renal microscopic abnormalities were observed.13 Tenofovir has a favorable safety profile in human trials with 1 large clinical trial, which showing no Fanconi syndrome or discontinuation from study due to tenofovir-related renal abnormalities.14 Data from the GS 902 and 903 studies of tenofovir indicated that ,1% of patients discontinued tenofovir treatment due to renal events.15 Fanconi syndrome was not listed as the cause of renal toxicity in these studies, and FS is considered a rare side effect. Despite its rarity, FS in associated with tenofovir has been well documented in various case series and reviews of literature. Zimmermann et al16 in his case series and review of the literature described 27 patients who developed tenofovir-associated acute renal failure with the mean duration of tenofovir therapy being 11 months (range, 1–29 months). Our patient had first received tenofovir in 2006 and had consistently been on a tenofovir-containing regimen for approximately 8 years before the development of FS. This has important clinical implications as FS can occur at any time during the course of treatment and needs to be considered in the differential diagnosis of any patient receiving tenofovir who develops proximal RTA irrespective of the duration of treatment. This late presentation could be from interaction of tenofovir with other medications. Tenofovir when combined with didanosine or a protease inhibitor has been associated with cumulative effects,17,18 and it is suspected that tenofovir with PIs can interact with renal organic anion transporters, leading to nephrotoxic tubular concentrations of tenofovir. Our patient was not on a combination containing a protease inhibitor, so this is not a possibility. Our patient was also on doxycycline for chronic suppression of osteomyelitis. Aminoglycosides have been American Journal of Therapeutics (2016) 23(2)
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e560
associated with FS, which is dependent on the duration of treatment and cumulative dose, but doxycycline has not been implicated as a causative agent.6 Also, it is highly unlikely that doxycycline was the offending agent as the patient recovered after discontinuing the tenofovir while the doxycycline was never discontinued. Complete or partial recovery is usually seen once tenofovir is discontinued11 as was seen in our patient. In summary, FS is a serious renal toxicity associated with the use of tenofovir, and there may be various factors that may trigger FS. This case illustrates tenofovir-associated Fanconi syndrome developing after prolonged exposure at any time. FS can occur at any time during the course of treatment and needs to be considered in the differential diagnosis of any patient receiving tenofovir who develops proximal RTA irrespective of the duration of treatment.
REFERENCES 1. Gallant JE, Deresinski S. Tenofovir disoproxil fumarate. Clin Infect Dis. 2003;37:944–950. 2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescent GL.pdf. Accessed May 27, 2014. 3. Nelson MR, Katlama C, Montaner JS, et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS. 2007;21:1273– 1281. 4. Malik A, Abraham P, Malik N. Acute renal failure and Fanconi syndrome in an AIDS patient on tenofovir treatment—case report and review of literature. J Infect. 2005; 51:E61–E65. 5. Izzedine H, Launay-Vacher V, Isnard-Bagnis C, et al. Drug-induced Fanconi’s syndrome. Am J Kidney Dis. 2003;41:292–309. 6. Ghiculescu RA, Kubler PA. Aminoglycoside-associated Fanconi syndrome. Am J Kidney Dis. 2006;48:e89–e93.
American Journal of Therapeutics (2016) 23(2)
Luni et al 7. Tanji N, Tanji K, Kambham N, et al. Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion. Hum Pathol. 2001;32:734–740. 8. Meier P, Dautheville-Guibal S, Ronco PM, et al. Cidofovirinduced end-stage renal failure. Nephrol Dial Transplant. 2002;17:148–149. 9. Cihlar T, Lin DC, Pritchard JB, et al. The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1. Mol Pharmacol. 1999;56:570–580. 10. Imaoka T, Kusuhara H, Adachi M, et al. Functional involvement of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir. Mol Pharmacol. 2007;71: 619–627. 11. Jao J, Wyatt CM. Antiretroviral medications: adverse effects on the kidney. Adv Chronic Kidney Dis. 2010;17:72–82. 12. Van Rompay KK, Brignolo LL, Meyer DJ, et al. Biological effects of short-term or prolonged administration of 9-[2(phosphonomethoxy) propyl] adenine (tenofovir) to newborn and infant rhesus macaques. Antimicrob Agents Chemother. 2004;48:1469–1487. 13. Biesecker G, Karimi S, Desjardins J, et al. Evaluation of mitochondrial DNA content and enzyme levels in tenofovir DF-treated rats, rhesus monkeys and woodchucks. Antiviral Res. 2003;58:217–225. 14. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292:191–201. 15. Winiarczyk M, Sikora A, Mikula T, et al. Nephrotoxicity of Tenofovir true or myth? HIV AIDS Rev. 2009;8:17–20. 16. Zimmermann AE, Pizzoferrato T, Bedford J, et al. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis. 2006; 42:283–290. 17. Irizarry-Alvarado JM, Dwyer JP, Brumble LM, et al. Proximal tubular dysfunction associated with tenofovir and didanosine causing Fanconi syndrome and diabetes insipidus: a report of 3 cases. AIDS Read. 2009;19:114–121. 18. Rollot F, Nazal EM, Chauvelot-Moachon L, et al. Tenofovirrelated Fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome: the role of lopinavir-ritonavir-didanosine. Clin Infect Dis. 2003;37:e174–e176.
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Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
