Center for HIV and Hepatogastroenterology, Duesseldorf; Germany
Received 7 July, 2004
Revised 15 August, 2004
Accepted 1 September, 2004
Sponsorship: This study was supported by an unrestricted grant from Gilead Sciences, Martinsried, Germany.
Tenofovir disoproxil fumarate (tenofovir) shares some of its molecular structure with adefovir, a nucleotide analogue that is limited in its clinical use by nephrotoxicity [1,2]. In particular, a dose and time-dependent development of a Fanconi-like syndrome was reported . In contrast, tenofovir has not shown overt nephrotoxic effects in clinical trials [4,5]. However, Fanconi's syndrome and renal failure induced by tenofovir has been reported in anecdotal cases after tenofovir was granted approval for the treatment of HIV infection [6–10]. In the present cross-sectional study we assessed the effect of tenofovir on glomerular and tubular renal function.
Patients treated with tenofovir (n = 82) were compared with patients on antiretroviral therapy never treated with tenofovir (n = 92) (Table 1). From each patient a blood sample was drawn, blood pressure was measured and 24-h urine was collected. Diabetes mellitus, hypertension as defined as systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 95 mmHg, liver cirrhosis or known renal disease were exclusion criteria.
Creatinine, urea, uric acid, cystatin C, sodium, potassium, calcium, phosphate and chloride were measured in serum. In urine collected over 24-h the excretion rate of total protein, creatinine, urea, uric acid, sodium, potassium, calcium, phosphate and chloride was analysed.
The glomerular filtration rate (GFR) was calculated on the basis of creatinine in urine collected over 24 h  or using serum cystatin C, a cationic low molecular weight (13 360 Mr) cysteine proteinase, which is an established renal clearance marker [12,13]. In addition, GFR was estimated using the modified Modification of Diet in Renal Disease Study (MDRD) formula: 186 × serum creatinine (mg/dl)−1.154 × age (years)−0.203 × 1.212 if black ×0.742 if female, which gives a normal range of 90–120 ml/min 1.73 m2 [14,15].
In the case of proteinuria greater than 130 mg/day a DISC-electrophoresis was performed to differentiate the origin of proteinuria. An increase in small molecules such as beta-2-microglobulin or alpha-1-microglobulin indicates tubular dysfunction and an increase in larger molecules such as immunoglobulin G, albumin or transferrin indicates glomerular dysfunction.
Statistical analysis was based on contingency tables. In addition a two-way analysis of variance with factors tenofovir and the previous use of indinavir including interactions was performed on different dependent variables (age, time on antiretroviral agents, sex). For computation SAS was used (The SAS System; SAS Institute, Cary, NC, USA).
Patients on tenofovir showed a lower mean GFR calculated by creatinine clearance (97 ± 49 ml/min 1.73 m2) or cystatin C clearance (86 ± 21 ml/min 1.73 m2) compared with control patients (107 ± 39 ml/min 1.73 m2) and (97 ± 20 ml/min 1.73 m2) (P < 0.05). An impaired GFR as estimated by creatinine clearance (normal range >90 ml/ml 1.73 m2) or cystatin C (normal range >80 ml/min 1.73 m2) was observed in 38 (46%) or 28 (34%) patients on tenofovir compared with 29 (32%) or 19 (21%) control patients (P = 0.04 for creatinine, P = 0.06 for cystatin C).
Creatinine clearance, as estimated by the MDRD formula based on serum creatinine, was not different in both groups (tenofovir 106 ± 54 ml/min 1.73m2 versus control 104 ± 22 ml/min 1.73m2, P = 0.375).
Patients on tenofovir had a higher mean protein content in urine (124 ± 110 versus 94 ± 55 mg/day, P = 0.03). In total, 24 patients on tenofovir (30%) versus five control patients (5%) had proteinuria greater than 130 mg/day (P < 0.001). The majority of patients showed a tubular pattern (14/24 versus 3/5). Combined tubular and glomerular proteinuria was found in seven out of 24 patients on tenofovir compared with one out of five control patients. A glomerular pattern was observed in three out of 24 patients on tenofovir and in one out of five control patients.
The excretion rate in urine of creatinine, urea, uric acid, sodium, potassium, calcium, phosphate and chloride were in the normal range and were not significantly different between both groups.
In the analysis of variance no association was found between an impaired GFR or proteinuria and sex, age, previous use of indinavir or time on antiretroviral drugs.
In one patient with marked proteinuria (170 mg/day), proteinuria was reversible after the discontinuation of tenofovir with a decrease to 93 mg/day 3 weeks after stopping.
No patient in the study fulfilled the criteria for nephrotic syndrome or Fanconi-like syndrome.
In conclusion, treatment with tenofovir was associated with a lower mean GFR as estimated by creatinine clearance or serum cystatin C. It has to be noted, however, that the mean GFR was still within the normal range. In addition, there was a higher number of patients with a pathological GFR calculated by creatinine clearance or cystatin C in the tenofovir group compared with control patients. Interestingly, these differences were not detected by creatinine clearance as calculated on the basis of serum creatinine using the MDRD formula. This method was recently used in some reports on the effect of tenofovir on renal function .
In addition, in the tenofovir-treated group an increased number of patients with significant proteinuria predominantly of tubular origin were observed. This pattern may support a mechanism related to the nephrotoxic effect of adefovir, which was also associated with tubular renal dysfunction. It has to be noted, however, that in contrast to the findings reported for adefovir [2,17] no enhanced renal loss of electrolytes was found in patients treated with tenofovir.
Other factors, such as exposure to indinavir, an antiretroviral agent with known nephrotoxic potential, time on antiretroviral drugs, sex or age did not change the association between tenofovir and a decreased GFR or proteinuria.
It has to be noted that the study is limited by its cross-sectional design, and prospective controlled studies are needed to confirm the observations. However, the value of this study is the application of sensitive markers of renal function. Mild nephrotoxic effects may be missed by the simple and convenient approach of the formula-based estimation of creatinine clearance based on serum creatinine and patient demographics.
In conclusion, treatment with tenofovir may induce mild renal dysfunction in a higher proportion of patients compared with patients never treated with tenofovir. Treatment with tenofovir may render the kidney more vulnerable to concomitant treatment with nephrotoxic drugs. Therefore, a detailed functional assessment of renal function should be included in the design of future trials including treatment with tenofovir.
1. Fisher EJ, Chaloner K, Cohn DL, Grant LB, Alston B, Brosgart CL, et al
. The safety and efficacy of adefovir dipivoxil in patients with advanced HIV disease: a randomized, placebo-controlled trial. AIDS 2001; 15:1695–1700.
2. ADHOC International Steering Committee. A randomized placebo-controlled trial of adefovir dipivoxil in advanced HIV infection: the ADHOC trial. HIV Med
3. Hannon H, Bagnis CI, Benhamou Y, Beaufils H, Sullivan M, Brosgart C, et al
. The renal tolerance of low-dose adefovir dipivoxil by lamivudine-resistant individuals co-infected with hepatitis B and HIV. Nephrol Dial Transplant 2004; 19:386–390.
4. Schooley RT, Ruane P, Myers RA, Beall G, Lampiris H, Berger D, et al
, and the Study 902 team. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS 2002; 16:1257–1263.
5. Cheng AK, Chen SS, Wulfsohn M, Toole JJ. 2 year long term safety profile of tenofovir DF (TDF) in treatment-experienced patients from randomized, double-blind, placebo-controlled clinical trials.
In: 9th European AIDS Conference (EACS)
. Warsaw, Poland, 2003 [poster number 7.3/7].
6. Verhelst D, Monge M, Meynard JL, Fouqueray B, Mougenot B, Girard PM, et al
. Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am J Kidney Dis 2002; 40:1331–1333.
7. Karras A, Lafaurie M, Furco A, Bourgarit A, Droz D, Sereni D, 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.
8. 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.
9. Schaaf B, Aries SP, Kramme E, Steinhoff J, Dalhoff K. Acute renal failure associated with tenofovir treatment in a patient with acquired immunodeficiency syndrome. Clin Infect Dis 2003; 37:e41–e43.
10. James CW, Steinhaus MC, Szabo S, Dressier RM. Tenofovir-related nephrotoxicity: case report and review of the literature. Pharmacotherapy 2004; 24:415–418.
11. Rapoport A, Husdan H. Endogenous creatinine clearance and serum creatinine in the clinical assessment of renal function. Can Med Assoc J 1968; 99:149–156.
12. Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 2002; 40:221–226.
13. Kazama JJ, Kutsuwada K, Ataka K, Maruyama H, Gejyo F. Serum cystatin C reliably detects renal dysfunction in patients with various diseases. Nephron 2002; 91:13–20.
14. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate GFR from serum creatinine: a new prediction equation. Modification of diet in renal disease group. Ann Intern Med 1999; 130:461–470.
15. Levey AS, Greene T, Kusek JW, Beck GJ. A simplified equation to predict glomerular filtration rate from serum creatinine [Abstract]. J Am Soc Nephrol 2000; 11:A0828.
16. Harris M, Zalunardo N, Bonner S, Werb R, Valyi M, Montaner JSG. Use of estimated glomerular filtration rate to predict renal toxicity in patients receiving tenofovir DF.
In: 11th Conference on Retroviruses and Opportunistic Infections
. San Francisco, USA, 2003 [poster 750].
17. Earle KE, Seneviratne T, Shaker J, Shoback D. Fanconi's syndrome in HIV+ adults: report of three cases and literature review. J Bone Min Res 2004; 19:714–721.
© 2005 Lippincott Williams & Wilkins, Inc.