Background and Incidence
Tenofovir disoproxil fumarate (Viread), which is a prodrug of the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir, is an integral component of most first-line and many salvage antiretroviral regimens. Advantages of tenofovir include once-daily dosing, proven efficacy in numerous clinical trials, and increased drug susceptibility from the most common NRTI resistance-associated mutation, M184V/I. Tenofovir, however, can cause renal toxicity, which most commonly manifests as a proximal tubule wasting disorder that can progress to Fanconi’s syndrome (generalized proximal tubular dysfunction).[,,] Less commonly, tenofovir can cause acute kidney injury or, rarely, nephrogenic diabetes insipidus from distal tubular injury.[,] Use of tenofovir is an independent predictor of chronic renal dysfunction and concern for tenofovir-induced renal dysfunction is a frequent reason for referral of HIV-seropositive persons to a Nephrology specialist.[,] In one longitudinal study with 10 years of follow-up, tenofovir use increased the risk of renal dysfunction by 63%. In a large analysis from the Veterans Health Administration, each year of tenofovir use increased the risk of developing proteinuria by 34%, of rapid decline in renal function by 11%, and of developing chronic kidney disease by 33%. Another large retrospective analysis compared tenofovir-including regimens to tenofovir-sparing regimens and found increased risk of proximal tubulopathy with tenofovir, with a hazard ratio of 1.95 at 52 weeks and 5.23 at 104 weeks. The presentation of tenofovir-induced proximal tubulopathy can range from mild and often subclinical to severe and life threatening. If tenofovir-induced nephrotoxicity is diagnosed and managed promptly, it is often reversible; thus, vigilant monitoring, early diagnosis, and prompt management are vital for reducing the risk of long-term complications from tenofovir.
Mechanism for Tenofovir-Induced Nephrotoxicity
Evidence suggests the mechanism of tenofovir-induced renal toxicity involves an accumulation of mitochondrial damage in proximal tubule cells. At the proximal tubule cells, tenofovir enters via the basolateral membrane through organic ion transporters (OAT) 1 and to a lesser extent OAT3; tenofovir exits to the apical cells primarily through the multidrug resistance-associated protein 4 (MRP4) (Figure 1). Renal biopsies in the setting of tenofovir-induced nephrotoxicity often reveal signs of acute tubular damage, including epithelial flattening, decreased number of mitochondria, and abnormal size and shape of mitochondria; these dysmorphic mitochondria can form large intracytoplasmic eosinophilic inclusions.[,,] The destruction of proximal tubule epithelial cells and mitochondria impairs the kidney’s ability to reabsorb certain molecules, thereby causing urinary wasting of substances like glucose, bicarbonate, protein, and phosphate into the urine. Thus, the most frequent clinical manifestations of tenofovir-associated proximal tubule injury include normal anion gap metabolic acidosis (from leakage of bicarbonate), proteinuria, glycosuria, and low serum phosphate (from elevated fractional excretion of phosphate). The estimated glomerular filtration rate (GFR) is affected to a variable degree and can remain normal, even in the setting of proximal tubulopathy. Notably, creatinine clearance alone is an insensitive marker of tenofovir-related proximal tubulopathy. Renal wasting of phosphate in this setting can lead to disordered bone mineralization or osteomalacia and patients may present with bone pain and may be at increased risk of fracture.[,]
Risk Factors for Tenofovir-Associated Nephrotoxicity
Certain individuals are at higher risk of tenofovir-induced proximal tubulopathy than others and not all who take tenofovir will develop this side effect. Investigators have identified multiple host factors associated with increased risk for tenofovir-associated nephrotoxicity: low body mass index, advancing age, lower CD4 count, baseline renal impairment, concomitant use of nephrotoxic drugs, and comorbid conditions, such as hypertension, diabetes, and hepatitis C virus infection.[,,,,] Many of these factors were also identified in a large cohort of HIV-infected women (Figure 2). Multiple studies have confirmed that renal dysfunction is more likely to occur when tenofovir is combined with a ritonavir (Norvir)-boosted protease inhibitor, as compared to when combined with other antiretroviral agents.[,,,] The increased risk of tenofovir renal toxicity when concomitantly administered with ritonavir most likely results from ritonavir induced increases in serum tenofovir levels; prior work suggested that tenofovir tubular cell levels increased via ritonavir inhibition of the MRP2 transporter, but this protein now is not thought to play a significant role in the efflux of tenofovir from the proximal tubule cells.[,] In addition, single nucleotide polymorphisms in proximal renal tubule transporter genes such as ABCC2, ABCC4, and ABCC10 may increase an individual’s risk of tenofovir-induced nephrotoxicity, though these tests are not widely available and are not generally used to guide clinical management.[,,]
Routine Monitoring for Tenofovir-Associated Nephrotoxicity
Because of the risk of tenofovir-induced kidney injury, multiple HIV treatment guidelines recommend baseline assessment of renal function as well as ongoing monitoring for signs of nephrotoxicity (Figure 3).[,,] According to Department of Health and Human Services (HHS) Adult HIV Treatment Guidelines and Infectious Disease Society of America (IDSA) HIV Primary Care Guidelines, all individuals should undergo testing of basic metabolic panel (BMP) for calculation of glomerular filtration rate (GFR) or creatinine clearance (CrCl), plus urinalysis to assess for baseline proteinuria, before starting antiretroviral therapy.[,] The IDSA HIV Renal Management guidelines recommend using the CKD Epidemiology Collaboration (CKD-EPI) equation to estimate GFR or the Cockroft-Gault equation to estimate creatinine clearance. If testing reveals evidence of baseline renal dysfunction, consideration should be given to avoiding tenofovir, particularly in combination with a boosted protease inhibitor. Abacavir is a common alternate NRTI that can be considered in this situation, assuming that baseline resistance, HLA-B5701 status, or other factors do not contraindicate the agent. If abacavir is not an option, NRTI-sparing regimens may be considered. The various guidelines agree with regular monitoring for development of tenofovir-induced renal dysfunction in those who are prescribed the drug, with some variability in recommended frequency of monitoring; overall, most guidelines agree with rechecking the basic metabolic panel (BMP) every 3 to 6 months along with urinalysis or other screen for proteinuria (such as urine albumin or protein/creatinine ratio) at least every 6 to 12 months and more frequently if abnormalities arise or if comorbidities suggest increased risk for renal side effects.[,,]
Evaluation of Suspected Tenofovir-Associated Nephrotoxicity
If a patient on tenofovir develops evidence of declining GFR or creatinine clearance, a new normal anion gap metabolic acidosis, or proteinuria on routine surveillance laboratories, recheck of those parameters along with additional testing for tenofovir-induced kidney dysfunction is indicated. Suggested additional testing includes serum creatinine, serum phosphate, urine creatinine, and urine phosphate (all on the same day) in order to calculate the fractional excretion of phosphate. The fractional excretion of phosphate (Figure 4) can vary depending on a number of factors and descriptions of what is considered normal vary, though it is generally agreed that a level below 5 to 10% is considered normal and a level above 20% is considered clearly abnormal. Interpretation of the fractional excretion of phosphate should be done in context of the serum level, since a fractional excretion of phosphate in the range of 5 to 20% may be relatively and inappropriately elevated in a patient with a low serum phosphate level. Moreover, in the setting of severe hypophosphatemia, a fractional excretion above 5% may represent abnormal urinary phosphate excretion.[,] When evaluating for tenofovir renal toxicity, a quantification of proteinuria with protein to creatinine ratio is also generally advised. If the diagnosis is still in question, further analyses can be obtained, including urine protein electrophoresis (UPEP) to look for spillage of small molecules like beta-2-microglobulin, or retinal binding protein (RBP). Beta-2-microglobulin and RBP are sensitive markers of proximal tubule dysfunction, but RBP may not be readily available to clinicians in all locations.[,,] If the diagnosis remains in question or if a patient develops significant renal dysfunction, referral to a Nephrologist is appropriate. In the era of modern antiretroviral therapy, tenofovir-induced renal dysfunction often must be differentiated from benign serum creatinine elevations that can occur with cobicistat (Tybost), dolutegravir (Tivicay), rilpivirine (Edurant), and trimethoprim, all of which may alter estimated GFR but not in actual GFR.[,] With all of these agents, serum creatinine generally rises 0.1 to 0.2 in the first 4 to 8 weeks of therapy and then stabilizes, and changes are not associated with other markers of proximal tubulopathy. Therefore, if other laboratories suggest a proximal tubule wasting syndrome or if GFR continues to decline beyond the expected amount or beyond the first 4 to 8 weeks, tenofovir toxicity must be considered and evaluated. Tracking the trajectory and magnitude of GFR changes and assessing for other evidence of proximal tubulopathy helps to make the distinction between tenofovir toxicity and expected serum creatinine changes from other agents. For patients initiating an agent that is known to increase serum creatinine without affecting actual GFR (such as cobicistat, rilpivirine, or dolutegravir), some guidelines suggest rechecking the serum creatinine 4 weeks after antiretroviral initiation and considering the 4-week serum creatinine value to be the new baseline. In addition, atazanavir (Reyataz) can cause nephrolithiasis and true renal dysfunction, so if tenofovir is combined with atazanavir and renal dysfunction ensues, both agents should be considered as potential causes.
Management of Tenofovir-Associated Nephrotoxicity
If the above work-up reveals abnormalities, a clinician must judge whether to change tenofovir to an alternate agent or continue with close monitoring. This decision generally involves weighing the degree of proximal tubule dysfunction versus other available options for antiretroviral therapy. If the only abnormality detected is mild proteinuria with all other parameters normal, continued use of tenofovir with regular monitoring may be reasonable and other causes of proteinuria should be evaluated. If, however, multiple parameters suggest proximal tubulopathy and alternative antiretroviral agents exist that are judged to be safe and effective to control a person’s HIV, then a change of therapy is indicated. The IDSA Renal Management guidelines recommend replacing tenofovir with an alternate agent if the GFR declines by more than 25% and to less than 60 mL/min/1.73 m2, particularly if there are signs of proximal tubule dysfunction. Renal dysfunction resolves in most, but not all, patients after discontinuation of tenofovir. In one analysis, at 22 months after discontinuation, renal function returned to normal in 59% of subjects, improved but did not normalize in 9.8%, and did not improve in 31%. In this study, normalization of renal function was associated with higher CD4 counts (nadir and current), suggesting a role for immune function in resolution of renal toxicity. The median time to normalization of renal function was 4 months (range 2 to 15.75 months) and the time to maximum improvement in those subjects whose renal function improved but did not resolve was 14 months (range 8.75 to 27.75 months). Duration of tenofovir administration prior to discontinuation correlates with likelihood of renal function recovery and rate of recovery. In the setting of proximal tubulopathy, an individual may need replacement of electrolytes and other supportive measures and rarely a person requires admission to the hospital for care. If alternative antiretroviral agents are not available or possible for an individual, close monitoring while on tenofovir may be considered if the abnormalities are mild, though the dose of tenofovir should be reduced in the setting of a moderate to severe decline in GFR (dose is reduced if the GFR declines below 50 mL/min). Aggressive management of comorbidities like hypertension and diabetes and avoidance of other nephrotoxic agents may help to prevent tenofovir renal toxicity.