Acute kidney injury caused by tenofovir disoproxil fumarate and diclofenac co‐administration

Abstract

ObjectivesThe renal elimination of tenofovir (TFV) may be subject to renal drug−drug interactions that may increase the risk of kidney injury. Case reports indicated that diclofenac might increase TFV-associated nephrotoxicity via a drug−drug interaction, leading to an increased intracellular TFV concentration in proximal tubular cells. MethodsA retrospective analysis of data for all patients from the Frankfurt HIV Cohort (FHC) who had diclofenac prescriptions between January 2008 and June 2012 was carried out. ResultsAmong 89 patients with diclofenac use, 61 patients (68.5%) were treated with tenofovir disoproxil fumarate (TDF) and 28 patients (31.5%) were treated with TDF-sparing combination antiretroviral therapy (cART). Thirteen patients (14.6%) developed acute kidney injury (AKI) shortly after initiating diclofenac treatment. AKI occurred exclusively in TDF-treated patients, although all had previously stable renal function. All cases were accompanied by new onset of at least two parameters indicating proximal tubular damage, such as normoglycaemic-glucosuria and hypophosphataemia. TFV-associated nephrotoxicity was demonstrated by renal biopsy in four cases. Additionally, 11.5% of patients on TDF treatment developed new-onset proximal tubular damage, while having a preserved glomerular filtration rate. In contrast, diclofenac did not affect renal function in patients with TDF-sparing cART, as only one case of isolated hypophataemia was observed in these patients. In univariate analysis, risk factors for AKI were TDF-containing cART (P = 0.0076) and pre-existing hypophosphataemia (P = 0.0086). ConclusionsDrug−drug interaction caused by diclofenac could exacerbate TFV-associated nephrotoxicity. Diclofenac should be used with caution in patients on TDF therapy, especially in those with hypophosphataemia. Our findings need to be confirmed in larger studies.Keywords: acute kidney injury, drug−drug interaction, Fanconi syndrome, HIV, nonsteroidal anti-inflammatory drugs, tenofovir IntroductionAcute kidney injury (AKI) is a common, often reversible complication with an estimated incidence of 2.7 to 5.9 per 100 person-years in HIV-infected out-patients [1][2][3][4] [3,7,8].Renal toxicity related to TFV is caused by proximal tubular injury that may present with various manifestations (hypophosphataemia, normoglycaemic-glucosuria, hypouricaemia, proteinuria and/or metabolic acidosis, including partial or complete Fanconi syndrome) attributable to impaired reabsorption of glomerular filtrate and nephrogenic diabetes insipidus, as well as AKI [9][10][11][12]. Tenofovir disoproxil fumarate (TDF) is a prodrug which is rapidly metabolized to TFV in plasma. TFV is eliminated unchanged by glomerular filtration (70-80%) as well as proximal tubular secretion (20-30%). TFV enters the proximal renal tubular cells via human organic anion transporter 1 (hOAT1) and is then actively secreted into the urine by the multidrug-resistance protein (MRP), mainly MRP4 [10,11,13,14].Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit dru...

The role of drug transporters in the kidney: lessons from tenofovir

“…In a study using HIV patients, co-administration of the non-steroidal anti-inflammatory drug diclofenac with tenofovir led to a high (14.6%) occurrence of acute kidney injury, compared to tenofovir treatment without diclofenac (0%; Bickel et al, 2013). Diclofenac is an inhibitor of SLC22A6 and ABCC4 and the increased frequency of acute kidney injury in the diclofenac-administered group may be due to inhibition of transporter-associated tenofovir renal excretion (El-Sheikh et al, 2007; Juhasz et al, 2013).…”

The Pharmacological and Physiological Role of Multidrug-Resistant Protein 4

“…Moreover, in another case report, a patient under long-term TFV treatment developed severe acute tubular necrosis, precipitated by the sudden start of diclofenac (Morelle et al, 2009). A retrospective analysis further demonstrated that more than half of patients given TFV developed proximal tubular damage shortly after initiating diclofenac treatment (Bickel et al, 2013). In addition, it is known that diclofenac, as well as other NSAIDs, can strongly inhibit MRP4-driven transport (Tian et al, 2005;El-Sheikh et al, 2007).…”

Advances in the pathogenesis of HIV-associated kidney diseases

“…107 However, the mechanism by which tenofovir (and other NtRTI) induce mitochondrial injury is not clear and it appears to involve a mechanism that is distinct from NRTI as it does not inhibit DNA polymerase-g. 111,112 These animal studies are supported by a recent case series demonstrating that inhibition of basolateral uptake of tenofovir by administration of probenecid seems to protect against tubular injury in patients with previous history of tenofovir-induced nephrotoxicity 113 and a case series of patient taking tenofovir who developed signs of tubular injury after starting diclofenac, which inhibits multidrug resistance-associated protein4 function. 114 The factors that regulate tenofovir uptake and secretion from tubular epithelial cells are summarized in Figure 5. The relative sensitivity of proximal tubules to NRTI-and NtRTI-induced toxicity is likely related to the extremely high energy needs in this nephron segment requiring abundant mitochondrial ATP generation and the presence of specific transporters in proximal tubular cells that facilitate intracellular accumulation of these medications.…”