Proximal tubular dysfunction and kidney injury associated with tenofovir in HIV patients: a case series

Abstract

BackgroundTenofovir disoproxil fumarate (TDF) may cause acute kidney injury and proximal tubular dysfunction. However, no detailed studies document urinary phosphate wasting as a marker of TDF-induced tubulopathy.MethodsRecords of HIV-infected patients with presumed TDF toxicity were reviewed. We describe the characteristics and clinical course of 15 patients who had documented elevated (>20%) fractional excretion of phosphate (FEphos).ResultsPatients were predominantly Caucasian and male (73 and 80%, respectively), with a mean age of 56 years (range 38–76). Of the 15 patients, 11 had a estimated glomerular filtration rate (eGFR) of >90 mL/min/1.732 at time of TDF initiation. The mean duration of TDF therapy prior to diagnosis of TDF toxicity was 64 months. Mean FEphos was 34% (range 20–62). The mean eGFR at TDF initiation was 104 mL/min/1.73 m2 [standard deviation (SD) 17.0] with a gradual decline to 69 mL/min/1.73 m2 (SD 19.0) by the time of TDF discontinuation. Of 10 patients with repeated FEphos after TDF discontinuation, 9 had improvement of their FEphos. Of these individuals, 6 had normalization of their FEphos. Estimated GFR improved in 12 patients after discontinuation of TDF, though importantly, none returned to their baseline eGFR.ConclusionsUrinary phosphate wasting is a sensitive marker for TDF-induced proximal tubulopathy and is associated with unrecognized and permanent renal function decline. Tubular dysfunction can develop after years of TDF therapy in those with normal kidney function at the time of drug initiation. This suggests that continuing vigilance be maintained in all those on TDF.

Nephrotoxicity Associated with Concomitant Use of Ledipasvir‐Sofosbuvir and Tenofovir in a Patient with Hepatitis C Virus and Human Immunodeficiency Virus Coinfection

“…The mechanism of TDF‐induced nephrotoxicity is not completely understood and is postulated to involve mitochondrial DNA depletion via inhibition of DNA polymerase ɣ and tubular injury caused by tenofovir accumulation in the proximal tubules. This accumulation may result from increased activity of the organic anion transport 1 transporter protein that facilitates uptake into the tubule or inhibition of the multidrug resistance protein transporters responsible for tenofovir efflux …”

“…The most common presentation of renal dysfunction associated with TDF is renal proximal tubulopathy that results in decreased reabsorption of electrolytes and subsequent proteinuria, glycosuria, renal potassium wasting with hypokalemia, and phosphaturia . TDF‐induced tubular dysfunction typically has a delayed onset and is at least partially reversible following discontinuation . Although the decline in renal function associated with TDF is often chronic, cases of acute injury with an onset ranging from 8 weeks to 96 months after initiation of TDF have been reported .…”

Clinical Pharmacology in HIV Therapy

“…Likewise and equally important, some of these agents have been shown to be directly nephrotoxic, inducing a variety of kidney disorders ranging from AKI, acute interstitial nephritis, kidney stones, crystalline nephropathy, and CKD to proximal and distal tubular kidney dysfunction (1,(6)(7)(8)(9)(10)(11). Understanding the pharmacologic characteristics of these agents is essential in this context.…”

HIV and kidney diseases: 35 years of history and consequences

“…Fractional excretion of phosphate showed a good performance as an early marker of tubular dysfunction, and should be incorporated as a tool of CKD prediction. Urinary phosphate wasting was a sensitive marker for tenofovir-induced proximal tubular dysfunction and was associated with unrecognized and permanent kidney function decline [109]. However, prediction risk models are not yet broadly implemented in routine clinical practice, although implementation has the potential to increase the safety of ART [110].…”