Tenofovir (Viread; Gilead, Foster City, CA) is a nucleotide analogue used in the treatment of HIV infection. 1 Tenofovir is extensively excreted by the renal route by means of glomerular filtration and active tubular secretion. 2 This drug is structurally close to adefovir and cidofovir, which are used in the treatment of hepatitis B infection and cytomegalovirus infection, respectively. 1,3 High doses of adefovir and cidofovir have been involved in renal injuries. 4 Moreover, 2 cases of Fanconi syndrome have been previously reported with cidofovir. 5,6 Until now, few cases of Fanconi syndrome and acute renal failure have been described with tenofovir. 7–10 We report 7 new cases of renal tubular injury in patients treated with tenofovir.
A 48-year-old HIV-infected woman had been treated with ritonavir/lopinavir, lamivudine, efavirenz, and tenofovir since August 2001. In addition, the patient received fenofibrate and pravastatin for dyslipidemia. Before starting tenofovir, her serum creatinine level was normal. In March 2002, laboratory tests showed phosphatemia at 0.39 mmol/L, proteinuria at 1.7 g/L, glycosuria at 27.5 mmol/L, and serum creatinine level at 88 μmol/L. Glycemia, creatine kinase, and aminotransferase levels were normal. One week later, the patient complained of paresthesia in the lower back and legs, leading to the discontinuation of pravastatin and fenofibrate. The pain persisted, however, and 1 week later, biologic test results remained abnormal. At that time, the tenofovir plasma level was 380 ng/mL (15 hours after drug administration). Urinary protein electrophoresis showed albumin of 26.3%, α1-glycoprotein of 24.5%, α2-glycoprotein of 24.7%, β-microglobulin of 10.8%, and γ-globulin of 13.7%. Chromatography of urinary amino acid showed severe hyperaminoaciduria with citrullinuria, compatible with tubulopathy. All antiretroviral agents were stopped. Clinical symptoms disappeared within 1 week, and laboratory abnormalities returned to baseline values within 3 months.
A 56-year-old HIV-infected woman had been treated with ritonavir/lopinavir, lamivudine, efavirenz, and tenofovir since May 2001. In addition, she received fenofibrate for dyslipidemia. Before starting tenofovir, her serum creatinine level was normal. In March 2002, the patient complained of pains in the legs and elbows. Laboratory tests showed phosphatemia at 0.72 mmol/L, proteinuria at 1.59 g/L, glycosuria at 7.7 mmol/L, and serum creatinine level at 78 μmol/L. Glycemia, creatine kinase, and aminotransferase levels were normal. Urinary protein electrophoresis showed albumin of 39.8%, α1-glycoprotein of 18.8%, β2-glycoprotein of 21.8%, β-microglobulin of 9%, and γ-globulin of 10.6%, compatible with renal tubulopathy. Only the tenofovir was stopped. The pains disappeared within 1 week, and laboratory abnormalities returned to baseline values within 3 months.
A 49-year-old man had been treated with didanosine, lamivudine, ritonavir, amprenavir, and tenofovir since August 2001. Before starting tenofovir, his serum creatinine level was normal. In May 2002, laboratory tests showed phosphatemia at 0.41 mmol/L, proteinuria at 1.15 g/L, glycosuria at 0.8 mmol/L, and serum creatinine level at 101 μmol/L. Glycemia and aminotransferase levels were normal. Urinary protein electrophoresis showed albumin of 47.4%, α1-glycoprotein of 10%, α2-glycoprotein of 21.1%, β-microglobulin of 9.2%, and γ-globulin of 12.3%. Only the tenofovir was stopped. Within 3 months, laboratory abnormalities normalized.
A 35-year-old HIV-infected woman, coinfected with hepatitis C virus (HCV), had been followed for Crohn disease since 1983. In May 2001, a new treatment combined abacavir, tenofovir, and ritonavir/lopinavir. When this tritherapy was started, the patient presented with persistent diarrhea related to her Crohn disease, her body weight was 38 kg, and her serum creatinine level was normal. With the new antiretroviral regimen, she presented a gain of body weight of 9 kg (47 kg). In April 2002, laboratory tests showed proteinuria at 1.86 g per 24 hours, glycosuria at 8.2 mmol/L, and serum creatinine level at 349 μmol/L. Only the tenofovir was stopped and replaced by lamivudine. Within 4 months, biologic parameters returned to normal values.
A 42-year-old HIV-infected woman had been treated with abacavir, ritonavir/lopinavir, lamivudine, and tenofovir since November 2001. Before starting tenofovir, her serum creatinine level was normal. Since the start of tenofovir, phosphatemia progressively decreased to a value of 0.23 mmol/L in September 2002, which led to phosphorus supplementation. Concomitantly, neurologic symptoms related to HIV gradually worsened. In March 2003, laboratory tests showed proteinuria at 0.78 g/L, normoglycemic glycosuria at 19.2 mmol/L, and serum creatinine level at 135 μmol/L. Within 10 months, the body weight of the patient decreased to 38 kg. At that time, the tenofovir plasma level, measured 16 hours after administration, was 1159 ng/mL. Only the tenofovir was stopped. Within 3 months, laboratory abnormalities significantly improved, and a body weight gain of 11 kg was observed.
A 41-year-old HIV-infected woman coinfected with HCV had received abacavir, nevirapine, and tenofovir since November 2001. Before starting tenofovir, her serum creatinine level was normal. In August 2002, the patient started treatment against HCV infection with ribavirin and pegylated (PEG)-interferon. In March 2003, the patient complained of paresthesia and myalgia in her lower limbs. Laboratory parameters showed phosphatemia at 0.51 mmol/L, proteinuria at 0.56 g/L, normoglycemic glycosuria at 0.3 mmol/L, and serum creatinine level at 84 μmol/L. In addition, anemia was observed with hemoglobinemia at 7.5 g/dL. Within 10 months, the body weight of the patient decreased to 40 kg. Urinary protein electrophoresis showed albumin of 29.1%, compatible with renal tubular injury. At that time, the tenofovir plasma level, measured 16 hours after administration, was 804 ng/mL. Only the tenofovir was stopped. Within 2 weeks, laboratory abnormalities normalized and a body weight gain of 4 kg was observed.
A 57-year-old HIV-infected man had been treated with lamivudine, abacavir, and tenofovir since June 2003. Before starting tenofovir, the patient received atazanavir with the same nucleoside reverse transcriptase inhibitors (NRTIs) but stopped after 3 months because of hyperglycemia. His serum creatinine level was normal. The patient received metformin and glibenclamide for hyperglycemia, rilmenidine for hypertension, and cotrimoxazole for Pneumocystis prophylaxis. Five weeks after initiation of the tenofovir, the patient suddenly developed acute renal failure, with serum creatinine level at 376 μmol/L, proteinuria at 2.7 g/L, (6.2 g per 24 hours) and hematuria. Other laboratory tests showed phosphatemia at 0.57 mmol/L, metabolic acidosis, and normoglycemic glycosuria at 31 mmol/L. A renal biopsy revealed tubulointerstitial nephropathy with a primarily lymphocytic infiltrate. Glomeruli were normal. All drugs were discontinued. One month later, serum creatinine level was at 193 μmol/L, with persistent proteinuria and glycosuria. Within 3 months, laboratory abnormalities significantly improved.
Demographic data are reported in Table 1, and biologic data are summarized in Table 2.
We present 7 cases of renal injury associated with tenofovir therapy. Some renal disorders observed in our patients are consistent with Fanconi syndrome, including proximal renal tubular acidosis, normoglycemic glycosuria, hypophosphatemia, hypouricemia, hypokalemia, generalized aminoaciduria, and proteinuria. 11 In some cases, acute renal failure may be observed.
Tenofovir, like cidofovir and adefovir, is an acyclic nucleoside phosphonate. 4 The 3 drugs are excreted by glomerular filtration and active tubular secretion. In the proximal tubule, cidofovir and adefovir interact with more than 1 renal transporter. They enter the renal cells on human renal organic anion transporter 1 (hOATI) and exit on multidrug resistance-associated protein 2 (Mrp-2). 3,11 Cidofovir and high-dose adefovir have been previously involved in renal dysfunction, and hOAT1 seems to play an active role in nephrotoxicity associated with these drugs. 4,12 Although efficiently transported by hOAT1, tenofovir shows weak cytotoxicity in isolated human proximal tubular cells. 4,13 In addition, a recent study showed that tenofovir does not seem to interfere with mitochondrial function, as suggested previously in studies relating nephrotoxicity to adefovir. 14,15 Finally, in a clinical trial, the safety profile of tenofovir was reported to be similar to that of placebo. 16
Our 7 patients had been treated with tenofovir for 5 to 64 weeks when the first symptoms of renal dysfunction occurred. In all patients, laboratory abnormalities rapidly improved after stopping the tenofovir. It seems unlikely that other drugs were responsible for renal dysfunction, because in 5 patients, only the tenofovir was discontinued.
A median decrease in creatinine clearance of 46% (range: 20%–78%) was observed. At baseline, some patients presented a decrease in creatinine clearance (calculated with the formula of Cockroft and Gault), despite serum creatinine levels showing normal ranges (see Table 2). Six patients had a low body weight. With these lightweight patients, serum creatinine level seems a poor parameter by which to evaluate renal function, and we recommend systematically calculating creatinine clearance.
Pharmacokinetics of tenofovir in HIV-infected patients showed median steady-state peak concentrations of 326 ng/mL and a trough value of about 40 ng/mL. 1 Plasma levels of tenofovir were measured in 3 patients at the time of renal dysfunction. Results showed high values (ie, 380 ng/mL, 1159 ng/mL, and 804 ng/mL [about 16 hours after drug administration], respectively). In animal models, nephrotoxicity seems to be dose dependent. Thus, this dose dependence could be one of the potential mechanisms of tenofovir-related renal complications.
In recent publications, 4 cases of Fanconi syndrome, 2 cases of acute renal failure, and 1 case of nephrogenic insipidus diabetes have been reported. 7–10,17 The time lapse between initiation of tenofovir and the onset of renal abnormalities is variable: 4 to 7 weeks in some cases 8,9,17 and several months in others. 7,10
A renal biopsy was performed in some published cases and showed acute tubular necrosis with normal glomeruli. 7–10 In our cases, only 1 renal biopsy was performed in patient 7. Results were in accordance with data reported in the literature (ie, tubulointerstitial nephropathy with normal glomeruli). In this patient, conventional immunofluorescence with anti-immunoglobulin and anti-C3 antibodies was negative. Furthermore, mild “tubular” proteinuria and glycosuria observed in other cases were consistent with a tubular source rather than with a glomerular leak.
In 5 cases, ritonavir was associated with antiretroviral regimens. This drug has been previously involved in acute renal failure. 18 Moreover, coadministration of ritonavir and lopinavir is known to increase pharmacokinetic parameters of tenofovir (maximum concentration [Cmax], +31%; minimum concentration [Cmin], +29%; area under the curve [AUC], +34%). 19 Ritonavir has been shown to be a potent inhibitor of Mrp-2–mediated transport. 20 As shown for adefovir and cidofovir, we suggest that Mrp-2 transports tenofovir outside renal tubules. Inhibition of Mrp-2 by ritonavir in patients taking tenofovir could be an explanation of the tubular dysfunction observed.
One patient (no. 3) has taken didanosine associated with tenofovir. Didanosine alone may be nephrotoxic, because 1 case of Fanconi syndrome has been reported. 21 Pharmacokinetic data showed a significant increase of bioavailability of didanosine when it is taken with tenofovir. 22 A recent publication reports the case of an HIV-infected patient with chronic renal insufficiency who developed acute renal failure and severe lactic acidosis when tenofovir was added to his antiretroviral regimen, including didanosine. 17
All our patients were extensively pretreated with NRTIs, which are known to induce mitochondrial defects. Even if an in vitro study showed that tenofovir does not induce mitochondrial toxicity, we speculate that after several months of therapy, tenofovir could worsen latent tubular injury in patients with a mitochondrial defect caused by previous treatment with NRTIs.
According to data presented here, occurrence of renal toxicity seems to focus on patients (1) with low body weight or altered renal function (low creatinine clearance) at baseline, (2) extensively pretreated with NRTIs and/or all nephrotoxic drugs, or (3) receiving ritonavir.
In conclusion, intensive renal monitoring, including creatinine clearance, proteinuria, and glycosuria, is essential at baseline and during treatment with tenofovir. Risk factors of nephrotoxicity and pertinence of therapeutic drug monitoring of tenofovir should be evaluated in prospective safety studies.
The authors thank Gilbert Deray, MD (Hôpital Pitié-Salpétrière, Paris), for his helpful comments and Gilles Peytavin, PharmD (Hôpital Bichat, Paris), for the measurement of tenofovir plasma levels.
1. Barditch-Crovo P, Deeks SG, Collier A, et al. Phase I/II trial of the pharmacokinetics, safety and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2001; 45:2733–2739.
2. Antoniou T, Park-Wyllie LY, Tseng AL. Tenofovir: a nucleotide analog for the management of human immunodeficiency virus infection. Pharmacotherapy. 2003; 23:29–43.
3. Cundy KC. Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. Clin Pharmacokinet. 1999; 36:127–143.
4. Cihlar T, Ho ES, Lin DC, et al. Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides Nucleic Acids. 2001; 20:641–648.
5. Vittecoq D, Dumitrescu L, Beaufils H, et al. Fanconi syndrome associated with cidofovir therapy. Antimicrob Agents Chemother. 1997; 41:1846.
6. Purohit N, Durr J, Lopez R. Cidofovir induced Fanconi syndrome and nephrogenic diabetes insipidus. Am J Kidney Dis. 2002; 39:26.
7. 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; 40:1331–1333.
8. Coca S, Perazella MA. Acute renal failure associated with tenofovir: evidence of drug-induced nephrotoxicity. Am J Med Sci. 2002; 324:342–344.
9. Créput C, Gonzalez-Canali G, Hill G, et al. Renal lesions in HIV-1-positive patient treated with tenofovir. AIDS. 2003; 17:935–937.
10. 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; 36:1070–1073.
11. Izzedine H, Launay-Vacher V, Isnard-Bagnis C, et al. Drug-induced Fanconi's syndrome. Am J Kidney Dis. 2003; 41:292–309.
12. Ho ES, Lin DC, Mendel DB, et al. Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1. J Am Soc Nephrol. 2000; 11:383–393.
13. Cihlar T, Birkus G, Greenwalt DE, et al. Tenofovir exhibits low cytotoxicity in various human cell types: comparison with other nucleoside reverse transcriptase inhibitors. Antiviral Res. 2002; 54:37–45.
14. Tanji N, Tanji K, Kambham N, et al. Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion. Hum Pathol. 2001; 32:734–740.
15. Birkus G, Hitchcock MJ, Cihlar T, et al. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. 2002; 46:716–723.
16. Schooley RT, Ruane P, Myers RA, et al. Tenofovir DF in antiretroviral-experienced patients: results from a 48-weeks, randomized, double-blind study. AIDS. 2002; 16:1257–1263.
17. Murphy MD, O'Hearn M, Chou S. Fatal lactic acidosis and acute renal failure after addition of tenofovir to an antiretroviral regimen containing didanosine. Clin Infect Dis. 2003; 36:1082–1085.
18. Deray G, Bochet M, Katlama C, et al. Néphrotoxicité du ritonavir. Presse Med. 1998; 27:1801–1803.
19. Kearney BP, Flaherty J, Wolf J, et al. Lack of clinically relevant drug-drug interactions between tenofovir DF and efavirenz, indinavir, lamivudine and lopinavir/ritonavir in healthy subjects. Presented at the 8th European Conference on Clinical Aspects and Treatment of HIV-Infection, Athens, 2001.
20. Gutmann H, Fricker G, Drewe J, et al. Interactions of HIV protease inhibitors with ATP-dependent drug export proteins. Mol Pharmacol. 1999; 56:383–389.
21. Crowther MA, Callaghan W, Hodsman AB, et al. Dideoxyinosine-associated nephrotoxicity. AIDS. 1993; 7:131–132.
22. Flaherty J, Kearney B, Wolf J, et al. Coadministration of tenofovir DF (TDF) and didanosine (ddI): a pharmacokinetic (PK) and safety evaluation [abstract I-1729]. Presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, December 2001.
Keywords:© 2004 Lippincott Williams & Wilkins, Inc.
tenofovir; tubular injury; nephropathy; HIV; Fanconi syndrome