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Tenofovir disoproxil fumarate (TDF) is the only nucleotide analogue currently available for the management of HIV infection. The efficacy of TDF was initially established in two clinical trials with antiretroviral (ARV)-experienced patients, in which the addition of TDF to stable background therapy resulted in a significant decrease in viral load relative to placebo, with a similar incidence of adverse effects . In addition, study GS-903 established TDF as a comparable alternative to stavudine when used in combination with lamivudine and efavirenz in ARV-naive patients, while eliciting less mitochondrial and metabolic toxicity . The convenience of once-daily administration coupled with a favourable toxicity profile has rendered TDF a welcome addition to the ARV arsenal. Importantly, unlike structurally related nucleotide analogues such as cidofovir and adefovir, clinically significant nephrotoxicity did not emerge as a treatment-limiting adverse effect of TDF in the clinical trials. Furthermore, the renal safety profile of TDF was similar to that of stavudine over 144 weeks of follow-up in study GS-903 .
However, post-marketing experience with TDF has raised the possibility that nephrotoxicity may be an uncommon but important adverse effect of this agent. Several case reports describing nephrotoxicity attributable to TDF have been published, with manifestations of Fanconi syndrome, nephrogenic diabetes insipidus and acute renal failure being reported [3–14]. To better describe the incidence of and potential risk factors for TDF-associated nephrotoxicity in routine clinical care, we performed a retrospective review of patients enrolled in the TDF Expanded Access Programme (EAP) in Toronto, Canada.
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The propensity to cause nephrotoxicity is a well-known trait of nucleotide analogues. The mechanism underlying this complication is thought to be related to their active cellular uptake by the human renal organic anion transporter-1 (hOAT-1) which is expressed on the cells of the proximal tubule . Although TDF is similar to other nucleotide analogues in its affinity for hOAT-1, in vitro data suggest that TDF is substantially less toxic to renal proximal tubule epithelial cells than cidofovir [16,17]. Also, no significant changes in mitochondrial DNA levels were observed in renal proximal tubule epithelial cells exposed to TDF concentrations ranging from 3 to 300 μm . Furthermore, evidence of renal toxicity in animals was observed at TDF exposures 2–20 times greater than those used in humans . Taken together, these findings suggest that TDF-mediated nephrotoxicity at therapeutic doses would be unlikely, a conclusion corroborated by the weight of clinical trial data published thus far. In two separate clinical trials with ARV-experienced patients, no patient developed grade 2 or higher changes in SCr during a mean of 58 weeks of follow-up . Furthermore, the renal safety profile of TDF was similar to that of stavudine during 144 weeks of follow up in ARV-naive patients, with <1% of patients per group developing grade 2 or higher nephrotoxicity . Finally, a retrospective review of patients receiving TDF identified 8.4% of patients as having attained a greater than 1.5-fold increase in SCr within 6 months of starting therapy, which is very similar to the incidence in our cohort .
The results of our study lend further support to the conclusion that TDF is a generally well-tolerated ARV agent from a renal standpoint. Only 15 patients had at least a 1.5-fold or greater increase in SCr during follow up, four of whom reached grade 1 nephrotoxicity. In addition, only four patients discontinued TDF because of suspected nephrotoxicity, three of whom appeared to have developed features consistent with Fanconi syndrome. Although increases in SCr were sometimes transient, sustained elevations from baseline remained in most patients for whom additional data were available. Longer term follow up will be necessary to determine whether a downward trend towards normal values would eventually occur or whether some degree of renal impairment persists in patients with TDF-associated nephrotoxicity. The possibility of irreversible changes in renal function is supported by evidence from case reports describing only a partial return towards baseline for SCr and findings of fibrotic lesions on kidney biopsy. However, these data are clearly limited by the anecdotal nature of case reports and the limited or unknown duration of follow up once TDF was discontinued.
Risk factors for TDF-mediated nephrotoxicity remain poorly defined. Because the risk of nephrotoxicity with TDF may be dose-related, the receipt of concomitant agents that increase TDF levels may inadvertently increase the risk of eliciting this adverse effect. The combination of lopinavir/ritonavir and TDF has been documented to increase TDF levels by approximately 30%, and may augment the potential for nephrotoxicity further by inhibiting the multidrug resistance protein (MRP)2-mediated efflux of TDF from the proximal tubule, thereby facilitating intracellular drug accumulation [21,22]. Virtually all cases of nephrotoxicity published thus far have been in patients who have been receiving TDF with either lopinavir/ritonavir or ritonavir in combination with another PI, lending some support to this theoretical association. However, in our univariate analysis, concurrent receipt of lopinavir/ritonavir was not significantly associated with a greater than 1.5-fold increase in SCr, a finding supported by other investigators [20,23]. Instead, only baseline SCr and creatinine clearance were significantly associated with nephrotoxicity in our study. We are unclear, however, why the results would suggest that patients with seemingly healthier kidneys at baseline were more predisposed to developing this complication. It is possible that, for patients with high starting levels of SCr, it is more difficult to attain our predefined endpoint of a 1.5-fold or higher increase from baseline. In the only other study to examine an association between baseline SCr and nephrotoxicity (in this case, time to onset of elevated SCr), a statistically significant association could not be demonstrated by univariate analysis . However, in a subanalysis of this study, the OR for renal toxicity was 1.19 per 1 mL/min decrease in glomerular filtration rate as calculated by the Levey modification of diet in renal disease (MDRD) formula . These results contradict those of our study, in that the OR for nephrotoxicity was 1.26 per 10 mL/min increase in creatinine clearance. It is unclear if the differences between the two cohorts are a result solely to the method used to estimate glomerular filtration rate, or if other factors are involved.
Hypophosphataemia in our study was generally a transient finding, and resulted in the discontinuation of TDF only as part of a larger spectrum of disturbances consistent with Fanconi syndrome. Similar conclusions regarding anomalies in serum phosphorus level were noted in studies of ARV-experienced patients. More recently, an analysis of 259 ambulatory HIV-infected patients did not identify TDF as being significantly associated with hypophosphataemia on univariate analysis, despite a higher frequency of this finding than noted in previous studies (30.7% of patients of receiving TDF). Instead, only cumulative time on combination ARV therapy and current use of lopinavir/ritonavir were significantly associated with hypophosphataemia in multivariate analysis . The significance and aetiology of hypophosphataemia remain unclear at present. Given the often transient nature of hypophosphataemia, patients with asymptomatic changes in serum phosphorus should have these levels reassessed periodically before withdrawing therapy with TDF. In the absence of clinical findings, continuing TDF with or without phosphorus supplementation would appear to be a reasonable course, assuming that alternative causes of hypophosphataemia and renal dysfunction are ruled out.
Abnormal findings on urinalysis were common in our patients, with grade 1 or 2 proteinuria being noted in 27% of patients with a follow-up urinalysis performed. The significance of these findings is presently unclear, and interpretation is limited by the lack of baseline and follow-up urinalyses. In addition, grade 1 or higher proteinuria was noted in 18% and 23% of ARV-naive patients receiving tenofovir or stavudine, respectively, in study GS-903 . Also, 3% of patients in each group had grade 3 or higher glucosuria. Thus, it is unclear whether proteinuria or glucosuria arises solely in the context of TDF, or whether other factors are important in the development of these abnormalities. Further study is needed to elucidate the significance of these findings.
Our study has several important limitations, including its retrospective nature and lack of a control group. In addition, the small number of events documented may have resulted in insufficient power to identify significant associations between baseline variables and the occurrence of nephrotoxicity. Also, our patients may have been at low risk for nephrotoxicity because of their well-preserved renal function at baseline. Still, although some cases of TDF-associated nephrotoxicity have occurred in the context of underlying kidney dysfunction, other authors have reported this side effect in patients with normal renal function prior to the initiation of TDF [4,5,14]. Also, it is difficult to fully account for the surprising association amongst baseline SCr, creatinine clearance and the development of nephrotoxicity. It is also possible that, by restricting the analysis to patients who had been on TDF for a minimum of 3 months, cases of nephrotoxicity with an earlier onset would have been missed and the safety of TDF from a renal perspective would be overestimated. However, the majority of cases reported thus far suggest that this adverse effect is not an early complication of TDF therapy. In addition, a small cohort study did not find any changes in SCr during the first 3 months of TDF therapy . It is, therefore, unlikely that we missed a large number of cases. Finally, the cohort was comprised largely of men, making it very difficult to apply similar conclusions regarding the renal safety of TDF to HIV-positive women. Still, the study provides some reassurance that, in most patients who receive therapy with a TDF-based regimen, the likelihood of clinically significant nephrotoxicity is relatively low.
In summary, although slight increases in SCr did occur after starting TDF, clinically significant nephrotoxicity was uncommon. However, because small increases in SCr may translate into large changes in glomerular filtration rate in patients with normal baseline renal function, our results suggest that tenofovir may not be completely free of nephrotoxic potential. Further research is necessary to determine the significance and aetiology of hypophosphataemia and proteinuria related to TDF.