In this study of kidney function among HIV-infected patients receiving tenofovir, older age and concurrent use of didanosine or amprenavir were significantly associated with increased risk of declining kidney function. Notably, these findings differed when the MDRD equation was used to estimate kidney function rather than the CG equation.
We had hypothesized that didanosine would be associated with declining GFR based on case reports [12,14–18,29–33]. The decline in kidney function found with didanosine was predominantly among patients with lower baseline weights, suggesting a dose-related effect. Additionally, this decline in GFR associated with didanosine was only detected using the CG equation, not with the MDRD equation; the latter may be less accurate among individuals with lower body weights . Further study is needed to determine the best method for estimating GFR among HIV-infected patients given the significant weight and body morphology changes observed in this group.
Case reports suggest that lopinavir/ritonavir, atazanavir, and ritonavir may be associated with tenofovir-associated kidney abnormalities [3,8,9,11,12,18,29,30]. It has been suggested that concurrent atazanavir or lopinavir/ritonavir may increase serum concentrations of tenofovir [35–37], and ritonavir may increase proximal tubule tenofovir concentrations . Others have suggested that patients treated with lopinavir/ritonavir often have more advanced HIV disease and thus a higher risk of adverse events . Our results agree with two prior studies that found no increase in tenofovir-associated kidney dysfunction among patients receiving lopinavir/ritonavir, atazanavir, or ritonavir [13,20]. However, we found a significant association between the coadministration of amprenavir and tenofovir and a decline in GFR, which has not been previously reported. We suspect that prior cohort studies have not detected this association because of the more limited use of amprenavir compared with, for example, lopinavir/ritonavir in many clinical settings. The basis for this association is unclear and additional studies are needed to confirm our findings as well as to examine possible mechanisms. Further characterization of interactions between amprenavir and drug efflux transporters may provide insight into mechanisms for this finding.
Low baseline weight was a significant risk factor for development of tenofovir-associated kidney dysfunction, suggesting that monitoring kidney function may be particularly important for lighter patients. Baseline body weight has not been included in most prior studies [39,40]. Our findings are consistent with several case reports [9,19,41] and the hypothesis that low body weight may lead to high tenofovir concentrations and increased risk of kidney impairment .
We did not find an association between tenofovir-associated kidney dysfunction and diabetes, hypertension, kidney stones, or HCV coinfection. However, the small numbers of patients with these conditions in our study sample limited our ability to examine these effects. As expected, older age was associated with increased risk of kidney abnormalities. We also found an increased risk among white patients when we used the MDRD equation to estimate GFR, but not when using the CG equation. This difference could reflect race-specific polymorphisms in drug membrane transporters; however, we suspect it is caused by the way race is included in the MDRD equation.
We observed two patterns of tenofovir-related kidney dysfunction. A few patients (seven) developed a severe decline in kidney function early in the course of treatment (3–4 months), while more patients (44) developed a mild to moderate decline occurring throughout tenofovir therapy. These findings are consistent with results from pooled clinical trial data (studies 902 and 907), which showed that 7% of patients had mild (grade 1) creatinine elevations, while only 1% discontinued tenofovir because of kidney-related effects, and only a single patient developed Fanconi syndrome . Another study that examined change in creatinine over 24 months also found that a large number of patients receiving tenofovir (42%) had a mild decline in kidney function, while a smaller number (4%) developed severe kidney dysfunction . The reason(s) for these patterns of toxicity associated with tenofovir is unknown, but it highlights the importance of designing future studies to detect both mild and severe changes in kidney function.
Reference methods for measuring GFR such as inulin are not suitable for routine clinical care . Therefore, clinicians rely on GFR estimates from equations incorporating clinical and demographic characteristics and serum creatinine. The validity of these equations has not been well established among HIV-infected patients . Single-sample serum creatinine level is the most widely used indirect estimate of GFR . However, creatinine levels are insensitive to even substantial declines in GFR , especially among individuals with HIV . The K/DOQI guidelines state that creatinine levels alone should not be used to assess kidney function . Despite their limitations, estimates of GFR using the CG and MDRD equations provide substantial improvement over just using serum creatinine .
We chose change in K/DOQI category as our primary measure of decline in GFR because both CG and MDRD equations have decreased accuracy at higher levels of GFR . A limitation of this approach is that small decreases in GFR in patients whose baseline value is close to a category cut-off will result in a category drop. We therefore conducted additional analyses requiring a change in category plus a decline in GFR of ≥ 20 ml/min per 1.73 m2. We also examined percentage change in GFR to decrease the impact of increased measurement variability of the CG and MDRD equations at higher levels of GFR . We used estimated GFR based on last creatinine value rather than an average value to maximize sensitivity of detecting decreasing levels over time. Another limitation of the CG equation is decreased accuracy among people with unusual body morphologies, such as those with obesity  or substantial muscle wasting . To explore this, we performed sensitivity analyses using the CG equation adjusted for body surface area and found no differences. Nevertheless, the impact of lipodystrophy (lipoatrophy and/or lipohypertrophy) on estimates of GFR will require additional studies.
The primary distinction between the CG and MDRD estimates of GFR is the inclusion of weight in the CG equation. The MDRD has been shown to overestimate GFR in underweight individuals , underestimate GFR at high GFR levels, and overestimate GFR at low levels . The CG equation may overestimate GFR at low GFR levels  and among patients with higher BMI . Therefore, using either equation for HIV-infected patients, who may have wide fluctuations in weight during the course of their disease, is problematic. Guidelines for HIV-infected individuals do not recommend the use of one method over the other .
Notably, the CG and MDRD equations identified groups of patients with kidney dysfunction that only partly overlapped (Fig. 1). Only four of the seven patients with severe kidney dysfunction identified by the CG equation were detected using the MDRD equation. Studies comparing the accuracy of the MDRD and CG formulae have been conducted in other patient populations, with mixed results that tended to favor MDRD [34,50,53–55]. The CG equation may provide a better estimate of GFR in HIV-infected patients, however, since it incorporates changes in weight commonly seen in this patient population. It is possible that the CG equation is imperfectly impacted by weight and that a decline in kidney function estimated by this method might represent changes in weight during follow-up. The findings were generally unchanged, however, when we accounted for change in weight in the multivariate model.
Strengths of our study included the ability to examine the comprehensive clinical data and the accurate antiretroviral treatment data captured in the UWHIS. Patients seen in routine care are more heterogeneous than those who enroll in clinical trials and have a broader range of characteristics and comorbid conditions. It is important to examine the effects of these characteristics on the outcome of tenofovir-associated kidney dysfunction and to determine the impact of these factors in real-world settings. As the cohort continues to be followed, additional information will become available with which to examine the effects of newer antiretroviral agents.
This study had a number of limitations. As with any observational study, unknown or unmeasured confounding is a concern. This was minimized by evaluating changes over time within individuals rather than comparing tenofovir-exposed patients with controls. Bias may be introduced by differences in the frequency of laboratory measurements in the clinical setting, but in our study, creatinine levels were routinely collected at 3–6 month intervals in the outpatient setting. Urine protein and phosphate levels were not routinely collected in the clinic and so were not available for analysis. The weights used in the CG equation were collected in a clinical setting by nursing staff prior to appointments, which may have resulted in less precision than weights collected using a research-based protocol. While the presence of HCV was noted, defined by the presence of HCV antibody or HCV RNA, we were unable to categorize HCV disease severity. Estimates of GFR relied on the use of the CG and MDRD equations but neither has been well validated among HIV-infected patients. Finally, we lacked any information regarding other potential risk factors that might impact tenofovir-related kidney dysfunction, such as genetic factors.
Tenofovir is a frequently prescribed antiretroviral medication because of its convenient dosing and favorable tolerability profile. Our study suggests that a significant proportion of patients who take tenofovir develop kidney dysfunction and that concomitant treatment with didanosine and amprenavir, as well as older age, increase this risk. The results of this study provide another reason to avoid didanosine with tenofovir [56,57]. Further study is needed to determine the appropriateness of using the CG and MDRD equations among HIV-infected patients, particularly for those who experience large shifts in weight or who have lipodystrophy. Additional large cohort studies are needed to define further the clinical and treatment factors affecting kidney function of HIV-infected patients taking regimens containing tenofovir.
The authors thank Dr Ashley Jefferson for his suggestions and the staff and patients of the University of Washington Harborview HIV clinic.
Sponsorship: This work was supported by grants from the Mentored Patient-Oriented Research Career Development Award NIAID Grant (AI-060464) and the University of Washington Center for AIDS Research NIAID Grant (AI-27757).
No authors have any affiliation with or financial involvement in any organization, matter, or materials discussed in this manuscript.
1. Working Group of the Office of AIDS Research Advisory Council. Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents. Bethesda, MD: AIDS Research Advisory Council; 2005. Accessed June 6, 2006, at http://aidsinfo.nih.gov
2. Izzedine H, Launay-Vacher V, Deray G. Antiviral drug-induced nephrotoxicity. Am J Kidney Dis 2005; 45:804–817.
3. Izzedine H, Isnard-Bagnis C, Hulot JS, Vittecoq D, Cheng A, Jais CK, et al
. Renal safety of tenofovir in HIV treatment-experienced patients. AIDS 2004; 18:1074–1076.
4. Schooley RT, Ruane P, Myers RA, Beall G, Lampiris H, Berger D, et al
. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS 2002; 16:1257–1263.
5. Gallant JE, Staszewski S, Pozniak AL, DeJesus 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.
6. Barditch-Crovo P, Deeks SG, Collier A, Safrin S, Coakley DF, Miller M, 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.
7. Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 2002; 46:716–723.
8. Gaspar G, Monereo A, Garcia-Reyne A, de Guzman M. Fanconi syndrome and acute renal failure in a patient treated with tenofovir: a call for caution. AIDS 2004; 18:351–352.
9. 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.
10. Barrios A, Garcia-Benayas T, Gonzalez-Lahoz J, Soriano V. Tenofovir-related nephrotoxicity in HIV-infected patients. AIDS 2004; 18:960–963.
11. 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.
12. Breton G, Alexandre M, Duval X, Prie D, Peytavin G, Leport C, et al
. Tubulopathy consecutive to tenofovir-containing antiretroviral therapy in two patients infected with human immunodeficiency virus-1. Scand J Infect Dis 2004; 36:527–528.
13. 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.
14. Krummel T, Parvez-Braun L, Frantzen L, Lalanne H, Marcellin L, Hannedouche T, et al
. Tenofovir-induced acute renal failure in an HIV patient with normal renal function. Nephrol Dial Transplant 2005; 20:473–474.
15. 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.
16. Coca S, Perazella MA. Rapid communication: acute renal failure associated with tenofovir: evidence of drug-induced nephrotoxicity. Am J Med Sci 2002; 324:342–344.
17. Creput C, Gonzalez-Canali G, Hill G, Piketty C, Kazatchkine M, Nochy D. Renal lesions in HIV-1-positive patient treated with tenofovir. AIDS 2003; 17:935–937.
18. 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.
19. Hansen AB, Mathiesen S, Gerstoft J. Severe metabolic acidosis and renal failure in an HIV-1 patient receiving tenofovir. Scand J Infect Dis 2004; 36:389–392.
20. Antoniou T, Raboud J, Chirhin S, Yoong D, Govan V, Gough K, et al
. Incidence of and risk factors for tenofovir-induced nephrotoxicity: a retrospective cohort study. HIV Med 2005; 6:284–286.
21. Kitahata MM, Reed SD, Dillingham PW, van Rompaey SE, Young AA, Harrington RD. Pharmacy-based assessment of adherence to HAART predicts virologic and immunologic treatment response and clinical progression to AIDS and death. Int J STD AIDS 2004; 15:803–810.
22. Crane HM, van Rompaey SE, Kitahata MM. Antiretroviral medications associated with elevated blood pressure among patients receiving highly active antiretroviral therapy. AIDS 2006; 20:1019–1026.
23. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31–41.
24. Levey AS, Greene T, Kusek J, Beck G. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 2000; 11:155A.
25. Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987; 317:1098.
26. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis
27. Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR
28. US National Institutes of Health. Appendix 6. Body mass index: how to measure obesity. In Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity In Adults: The Evidence Report
. [NIH Publication 98-4083
.] Bethesda, MD: National Institutes of Health; 1998. pp. 139–140.
29. 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.
30. 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.
31. Saumoy M, Vidal F, Peraire J, Sauleda S, Vea AM, Vilades C, et al
. Proximal tubular kidney damage and tenofovir: a role for mitochondrial toxicity? AIDS 2004; 18:1741–1742.
32. Hussain S, Khayat A, Tolaymat A, Rathore MH. Nephrotoxicity in a child with perinatal HIV on tenofovir, didanosine and lopinavir/ritonavir. Pediatr Nephrol 2006; 21:1034–1036.
33. Crowther MA, Callaghan W, Hodsman AB, Mackie ID. Dideoxyinosine-associated nephrotoxicity. AIDS 1993; 7:131–132.
34. Froissart M, Rossert J, Jacquot C, Paillard M, Houillier P. Predictive performance of the modification of diet in renal disease and Cockcroft–Gault equations for estimating renal function. J Am Soc Nephrol 2005; 16:763–773.
35. Zimmermann AE, Braden G, Pizzoferrato T. Reply to Winston and Shepp and to Lanzafame et al
. Clin Infect Dis
36. Jullien V, Treluyer JM, Rey E, Jaffray P, Krivine A, Moachon L, et al
. Population pharmacokinetics of tenofovir in human immunodeficiency virus-infected patients taking highly active antiretroviral therapy. Antimicrob Agents Chemother 2005; 49:3361–3366.
37. Kearney BP, Mathias A, Mittan A, Sayre J, Ebrahimi R, Cheng AK. Pharmacokinetics and safety of tenofovir disoproxil fumarate on coadministration with lopinavir/ritonavir. J Acquir Immune Defic Syndr 2006; 43:278–283.
38. Winston JA, Shepp DH. The role of drug interactions and monitoring in the prevention of tenofovir-associated kidney disease. Clin Infect Dis 2006; 42:1657–1658 [letter].
39. Mauss S, Berger F, Schmutz G. Antiretroviral therapy with tenofovir is associated with mild renal dysfunction. AIDS 2005; 19:93–95.
40. Julg BD, Bogner JR, Crispin A, Goebel FD. Progression of renal impairment under therapy with tenofovir. AIDS 2005; 19:1332–1333.
41. Masia M, Gutierrez F, Padilla S, Ramos JM, Pascual J. Severe toxicity associated with the combination of tenofovir and didanosine: case report and review. Int J STD AIDS 2005; 16:646–648.
42. Ruane PJ, DeJesus E. New nucleoside/nucleotide backbone options: a review of recent studies. J Acquir Immune Defic Syndr 2004; 37(Suppl 1):S21–S29.
43. El Sahly HM, Teeter L, Zerai T, Andrade RA, Munoz C, Nnabuife C, et al
. Serum creatinine changes in HIV-seropositive patients receiving tenofovir. AIDS 2006; 20:786–787.
44. Gaspari F, Perico N, Remuzzi G. Application of newer clearance techniques for the determination of glomerular filtration rate. Curr Opin Nephrol Hypertens 1998; 7:675–680.
45. Gupta SK, Eustace JA, Winston JA, Boydstun II, Ahuja TS, Rodriguez RA, et al
. Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2005; 40:1559–1585.
46. Deinum J, Derkx FH. Cystatin for estimation of glomerular filtration rate? Lancet 2000; 356:1624–1625.
47. Norden G, Bjorck S, Granerus G, Nyberg G. Estimation of renal function in diabetic nephropathy. Comparison of five methods. Nephron 1987; 47:36–42.
48. Huang E, Hewitt RG, Shelton M, Morse GD. Comparison of measured and estimated creatinine clearance in patients with advanced HIV disease. Pharmacotherapy 1996; 16:222–229.
49. 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.
50. Coresh J, Stevens L. Kidney function estimating equations: where do we stand? Curr Opin Nephrol Hypertens 2006; 15:276–284.
51. Delanaye P, Radermecker RP, Rorive M, Depas G, Krzesinski JM. Indexing glomerular filtration rate for body surface area in obese patients is misleading: concept and example. Nephrol Dial Transplant 2005; 20:2024–2028.
52. Rigalleau V, Lasseur C, Perlemoine C, Barthe N, Raffaitin C, Liu C, et al
. Estimation of glomerular filtration rate in diabetic subjects: Cockcroft formula or Modification of Diet in Renal Disease Study equation? Diabetes Care 2005; 28:838–843.
53. Bostom AG, Kronenberg F, Ritz E. Predictive performance of renal function equations for patients with chronic kidney disease and normal serum creatinine levels. J Am Soc Nephrol 2002; 13:2140–2144.
54. Pierrat A, Gravier E, Saunders C, Caira MV, Ait-Djafer Z, Legras B, et al
. Predicting GFR in children and adults: a comparison of the Cockcroft–Gault, Schwartz, and Modification of Diet in Renal Disease formulas. Kidney Int 2003; 64:1425–1436.
55. Poggio ED, Nef PC, Wang X, Greene T, Van Lente F, Dennis VW, et al
. Performance of the Cockcroft–Gault and modification of diet in renal disease equations in estimating GFR in ill hospitalized patients. Am J Kidney Dis 2005; 46:242–252.
56. Barrios A, Rendon A, Negredo E, Barreiro P, Garcia-Benayas T, Labarga P, et al
. Paradoxical CD4 T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine. AIDS 2005; 19:569–575.
57. Barreiro P, Soriano V. Suboptimal CD4 gains in HIV-infected patients receiving didanosine plus tenofovir. J Antimicrob Chemother 2006; 57:806–809.