To evaluate tenofovir-related nephropathy, we quantified calculated glomerular filtration rates (GFR) and renal tubular function in 46 tenofovir-treated patients and 25 without tenofovir. We also analysed patients who stopped tenofovir for drug-related nephrotoxicity at our clinic. Tenofovir use combined with non-nucleoside reverse transcriptase inhibitors, but not with protease inhibitors, resulted in a significant increase in calculated GFR. Tenofovir use was associated with significantly lower phosphatemia and a marginally increased fractional excretion of uric acid, but no other signs of tubulopathy.
aDivision of Infectious Diseases, University Hospital, Berne, Switzerland
bDepartment of Nephrology and Hypertension, University Hospital, Berne, Switzerland.
Received 27 September, 2006
Revised 6 March, 2007
Accepted 16 March, 2007
As a result of its favourable efficacy and safety profile, tenofovir has become a key component in combined antiretroviral therapy (ART) . Tenofovir use has recently been associated with Fanconi-like syndromes [2–5] and impaired glomerular filtration, as demonstrated by lowered creatinine clearance [2,6–8]. Tenofovir is thought to accumulate in the proximal tubular cells causing electrolyte losses as a result of impaired tubular reabsorption, renal tubular acidosis or defects in vitamin D hydroxylation [3–5,8,9]. Also, tubular creatinine secretion may be impaired [10,11]. To investigate tenofovir-related nephropathy further, we quantified renal function in a cross-sectional analysis and evaluated patients with suspected tenofovir-related nephrotoxicity.
Between September 2005 and April 2006 we consecutively evaluated all patients treated for at least one month with regimes including tenofovir plus non-nucleoside reverse transcriptase inhibitors (NNRTI; group 1, n = 21), tenofovir plus protease inhibitors (PI; group 2, n = 25), and tenofovir-sparing NNRTI-based treatments (n = 25). Both patients on their first combined ART and pretreated individuals were included. Calculated glomerular filtration rates (GFR) were established using the ‘modification of diet in renal disease’ formula  comparing calculated GFR before starting the current combination ART (baseline) with the values at the cross-sectional evaluation on treatment. Renal tubular function (Fig. 1) was assessed on the basis of the measurement of sodium, potassium, chloride, calcium, phosphate, protein, glucose, uric acid, protein, urea nitrogen, bicarbonate, creatinine and the osmolarity in serum and spot urine. Correlations of renal parameters with age, sex, race, body weight, time since HIV diagnosis, time on combination ART, CD4 cell stratum, time on tenofovir and co-medication with didanosine or cotrimoxazole were tested.
Furthermore, we identified all individuals who had changed combination ART because of nephrotoxicity at our clinic and evaluated the role of tenofovir.
Tenofovir-treated patients had significantly lower nadir CD4 cell counts, a longer duration of combination ART and a higher rate of symptomatic HIV infection and cotrimoxazole prophylaxis than tenofovir-naive patients. The median baseline calculated GFR was 104.9 ml/min for group 1 and 100.3 ml/min for group 2, significantly less than the tenofovir-sparing group with 121.0 ml/min (P = 0.03). Nine (19.6%) and one (2.1%) patients had a baseline calculated GFR less than 90 and less than 60 ml/min, respectively. Baseline calculated GFR inversely correlated with the duration of previous combination ART (P = 0.01) and symptomatic HIV infection (n = 49; P = 0.01), but not with the time since HIV diagnosis, nadir CD4 cell count, age, race, body mass index or cotrimoxazole co-medication.
The patients in groups 1 and 2 had been treated with tenofovir for a median of 15 months. Combined treatment with tenofovir and NNRTI resulted in a 16 ml/min increase in the calculated GFR (P = 0.001), whereas no change occurred in the tenofovir plus PI group (P = 0.9). In patients treated with tenofovir and cotrimoxazole (n = 12), the calculated GFR dropped by 1.9 ml/min, whereas tenofovir treatment without cotrimoxazole (n = 34) was associated with an increase of 11.1 ml/min (P = 0.06). Tenofovir treatment was associated with significantly lower mean phosphatemia (0.99 versus 1.14 mmol/l; P = 0.01) and an increased fractional excretion of uric acid (7.8 versus 6.6%; P = 0.05), but not of phosphate (12.8 versus 11.7%; P = 0.5). Distal tubular function parameters did not differ significantly between the groups (Fig. 1).
Of 662 patients receiving combination ART since May 2002 at our clinic, 246 (37%) were treated at least once with tenofovir for a median of 12 (interquartile range 4–26) months. Treatment discontinuation as a result of suspected drug-related nephrotoxicity occurred in 11 out of 622 patients (1.8%), and was related to indinavir in eight and to tenofovir in three patients. The latter all had low baseline calculated GFR (28, 43 and 64 ml/min) and tenofovir-independent causes of renal deterioration (systemic lupus erythematosus, sepsis and HIV-associated nephropathy). Two patients experienced tenofovir-associated drops in phosphatemia.
In the cross-sectional analysis, even close monitoring after a median exposure time of 15 months did not reveal significant tenofovir-related tubulopathy (Fig. 1). In earlier reports , tenofovir-related tubulopathy occurred well within the observation period of our study, after a median of 11 (range 1–29) months . The tenofovir-associated increase in the fractional excretion of uric acid suggests proximal tubulopathy, which may have escaped detection by fractional excretion of phosphate because most patients were not fasting when sampling was performed. The fractional excretion of phosphate correlated with renal urea nitrogen excretion as a surrogate for phosphate intake. The risk factors reported in the literature, low body weight and co-medication with boosted PI or didanosine [5,13], did not promote tenofovir toxicity in our setting.
We observed significant differences in calculated GFR between our groups, both at baseline and under tenofovir. The lower baseline GFR in patients with a longer duration of ART and more advanced HIV disease may indicate a negative impact of both antiretroviral therapy and severe immunodeficiency with its complications. Advanced immunosuppression has been associated with impaired renal function . The fact that tenofovir did not impair the calculated GFR in our patients may be related to the absence of preexisting nephropathy. Combining tenofovir with an NNRTI even increased GFR to values found in our tenofovir-naive patients. This contrasts with an earlier study that described a small but significant increase in GFR in controls, but not in tenofovir-treated patients . Without evidence of other significant differences between groups 1 and 2, the lack of an increase in the calculated GFR in group 2 may indicate some nephrotoxicity of tenofovir co-administered with PI, as suggested earlier . Gallant et al.  documented a larger decrease in GFR in tenofovir-treated patients compared with a tenofovir-sparing regime. Remarkably, their tenofovir group included significantly more patients treated with a boosted PI. As cotrimoxazole blocks tubular creatinine secretion, it can further impair the calculated GFR without reducing glomerular filtration. We observed a trend towards lower GFR values in patients treated with tenofovir and cotrimoxazole.
Tenofovir was stopped in 1.5% of patients because of suspected drug-related nephrotoxicity. All affected patients had severely impaired baseline renal function.
We conclude that without preexisting nephropathy significant tenofovir-related tubular dysfunction is rare. Co-medication with NNRTI may be more favourable for the calculated GFR than a combination with PI. Considering that up to 35% of urinary creatinine can be excreted through the tubulular system [10,11], the preserved tubular function among our patients could explain why we did not observe an impairment of calculated GFR.
The authors would like to thank all the patients who consented to this evaluation.
Conflicts of interest: H.F. has participated in advisory boards of Abbott, GSK, BMS, Roche, Gilead, MSD, and Boehringer-Ingelheim. The institution of H.F., C.A.F., A.C. and S.Z. has received unrestricted educational grants from Abbott, GSK, BMS, Roche, Gilead, MSD, and Boehringer-Ingelheim.
1. Hammer SM, Saag MS, Schechter M, Montaner JSG, Schooley RT, Jacobsen DM, et al
. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society – USA panel. JAMA 2006; 296:827–843.
2. Peyriere H, Reynes J, Rouanet I, Daniel N, De Boever CM, Mauboussin JM, et al
. Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases. J Acquir Immune Defic Syndr 2004; 35:269–273.
3. 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.
4. Rollot F, Nazal EM, Chauvelot-Moachon L, Kelaidi C, Daniel N, Saba M, et al
. Tenofovir-related 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.
5. Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis 2006; 42:283–290.
6. Gallant JE, Staszewski S, Pozniak F AL, De Jesus E, Suleiman JM, Miller MD, 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.
7. Heffelfinger J, Hanson D, Voetsch A, McNaghten A, Sullivan P. Renal impairment associated with the use of tenofovir. In: 13th Conference on Retroviruses and Opportunistic Infections. Denver, CO, USA. 5–8 February 2006, Abstract 779.
8. 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.
9. Izzedine H, Launay-Vacher V, Deray G. Renal tubular transporters and antiviral drugs: an update. AIDS 2005; 19:455–462.
10. Black R. Rose and Black's clinical problems in nephrology. Boston: Little, Brown and Company; 1996.
11. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function – measured and estimated glomerular filtration rate. N Engl J Med 2006; 354:2473–2483.
12. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130:461–470.
13. Day SL, Leake Date HA, 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; 38:301–304.
14. Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005; 40:1194–1198.