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Tenofovir Nephrotoxicity: Focusing Research Questions and Putting Them into Clinical Context
EDITORIAL COMMENTARY
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The Journal of Infectious Diseases Jan 1, 2008;197:7-9
Lynda Anne Szczech
Duke University Medical Center, Durham, North Carolina
Potential conflicts of interest: L.A.S. is a member of the speakers' bureau of and is a consultant to GlaxoSmithKline, is a member of the speakers' bureau of and is a consultant to Gilead, and is a member of the speakers' bureau of and has received research support from Abbott.
(See the article by Goicoechea et al., on pages 102-8.)
Reprints or correspondence: Dr. Lynda Anne Szczech, Duke University Medical Center, Box 3646, Durham, NC 27710 (szcze001@mc.duke.edu).
Multiple reports have indicated that the antiretroviral drug tenofovir has renal toxicity [1-9]. However, beyond simply identifying the existence of this potential toxicity, the key clinical questions that we as providers rely on to assist us in understanding which patients are at highest risk and how often to assess for toxicity have not really been answered. The study by Goicoechea et al. [10] in this issue of the Journal takes a key step in helping us to address at least part of this first question. Moreover, this study raises many other points worthy of discussion.
Goicoechea et al. compared kidney function over time among 3 cohorts of patients receiving tenofovir disoproxil fumarate (TDF) plus a ritonovir_boosted protease inhibitor (PI), TDF plus a nonnucleoside reverse_transcriptase inhibitor (NNRTI), and regimens not containing TDF. By use of either the Cockcroft_Gault or the Modification of Diet in Renal Disease equation, a greater decline in kidney function was seen among those persons receiving TDF and a ritonovir_boosted PI than among those in the other 2 groups. Of key interest is that the other 2 groups (i.e., those receiving TDF and an NNRTI and those not receiving TDF) also experienced decrements in their kidney function over time.
Tenofovir toxicity happens. Our understanding of it is in its early stages. Important questions still requiring answers include:
· Who is at risk?
· How frequently is it seen?
· Are there signs earlier than an elevation in creatinine level?
· How is it diagnosed?
Secondary analyses from clinical trials comparing antiretroviral regimens suggest that the risk of tenofovir toxicity is low (1%-2%) among those enrolled in clinical trials [11, 12]. However, the generalizability of estimates of safety events from trials need to be carefully considered, for 2 reasons. First, clinical trials frequently limit enrollment to subjects who do not have competing risks for outcomes that may not be affected by the therapy. For example, it would make little sense to enroll persons with lung cancer into a trial comparing coronary artery stents. Because renal disease and most risk factors for renal disease could be considered competing [13-15], it is appropriate that such persons might be excluded from the trials, but it is unfortunate in that it likely results in an underestimate of risk (the extent is unknown at this point). Second, even taken at face value in the populations enrolled in clinical trials, such trials are rarely powered to provide estimates of safety end points. So while these clinical_trial data may comfort us in that there are certain populations at low risk for toxicity, the risks in other groups and in settings in which patients are not monitored as closely as clinical trials will clearly be higher.
Case series documenting toxicity related to tenofovir include both acute renal failure and Fanconi syndrome and have incited much concern about the cumulative risk of tenofovir toxicity in "real life" [1-9]. However, without a true assessment of the denominator (the number of persons receiving a tenofovir_containing regimen), this concern cannot be translated into a measurement of risk and puts us no closer to deriving policies that balance safety with cost and with practicality in screening or in affecting early cases of toxicity.
As a community of providers (academic, private practice, and industry), we need to recognize that we need more information, more guidance, and more answers. We need to assess what data we have, combine them, and provide evidence_based information concerning the risks that our patients experience. We need to recognize that the risk is likely not homogeneous among the universe of patients who require antiretroviral therapy but that it probably varies from quite low to high in various subgroups. Goicoechea et al. add substantially to our information on this subject, but we still have so many questions yet to answer.
As a nephrologist, I think the biggest practical problem I face is not having sufficient detail about who is at risk and how to reliably and specifically diagnose a case of tenofovir toxicity. It is clear that persons with HIV infection as a group are aging and are developing increasing numbers of comorbidities. Kidney disease has increased and will likely continue to increase in this population [16]. If we biopsied the kidneys of everyone whose creatinine level rose from 1 to 1.5 mg/dL, the issue that I raised above would not be a concern-whenever a patient experienced such an increase, we would biopsy, know the histology, and treat or change therapy appropriately. But in medicine (particularly nephrology), we "play the odds." If a person with type 2 diabetes mellitus who had received the diagnosis 5 years ago and had had proteinuria (4 g) for several years experienced an elevation in creatinine level from 1 to 1.5 mg/dL, the odds suggest that diabetic nephropathy would be the likely cause, and therefore its treatment should be the primary focus. In the circumstance of renal disease in HIV infection, disruption of any successful antiretroviral regimen that is resulting in the suppression of viral replication may not make sense without further investigation to ensure that the rise in creatinine level was not simply the result of progression of the underlying kidney disease. However, the frequency of a case as straightforward as this is clearly much lower than we would like, and, without knowledge of how to diagnose toxicity, we may disrupt some component of successful regimens without adequate cause and miss the opportunity to treat non-medication_related kidney diseases at an early stage.
Having said that, as a nephrologist, tubular toxins never make me happy. I think about my kidneys every time I take a nonsteroidal anti_inflammatory drug. Yet the attention generated by considerations of tenofovir toxicity can benefit our patients in other ways, including by raising awareness about kidney disease in general. This attention has brought about an enthusiasm to be proactive in assessing kidney health. With that enthusiasm, however, the following will most certainly happen, and we, as a community dedicated to the health of our patients, need to be prepared for it:
· Screening with urine dipsticks will find more proteinuria than we expected.
· Regular checks of serum creatinine levels will find more kidney disease earlier. Some of this kidney dysfunction will be related to tenofovir toxicity, and some will not.
When proteinuria and evidence of decreased kidney function is found, we need to be prepared with the appropriate diagnostic and therapeutic plans. The knowledge that angiotensin_converting enzyme (ACE) inhibitors and angiotensin_receptor blockers benefit most patients with kidney diseases is relatively widespread within most subspecialties of internal medicine (including infectious diseases), but more subtle points-such as how to manage an increase in creatinine level from 1.4 to 1.8 mg/dL after the initiation of an ACE inhibitor or the threshold for blood_pressure and blood_sugar control in someone with kidney disease and hypertension or diabetes mellitus-may not be as well understood.
With the improved survival and resultant aging of persons with HIV infection as a population, we are at a happy but critical juncture in the management of chronic HIV infection. There needs to be a considerable educational cross_pollination between the subspecialties of infectious diseases and nephrology. With the rapid development of newer therapeutic strategies for HIV infection and the changing natural history of treated infection, it is very likely that other medical subspecialties may also need further education to make them more fully informed regarding the risks and benefits of the components of antiretroviral regimens. Similarly, it must be recognized that providers of care for HIV infection are often the default primary_care providers for their patients and require knowledge that extends beyond infectious diseases. Nephrologists understand this unexpected increase in scope of work, because we are in a similar situation with patients who require dialysis. We sympathize and can help, if asked.
References
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