tenofovir nephrotoxicity

A study just published looked at tenofovir disoproxil fumarate (TDF) renal toxicity, finding that urine dipstick evaluation is inadequate (see hiv tenofovir nephrotoxicity AIDS2015 in dropbox, or AIDS 2015, 29:941–946). details:

--43 patients with TDF nephrotoxicity (mean age 54.7, 53% men, 37% white/32% african-american/19% latino), and having biopsies showing proximal tubular injury and typical mitochondrial abnormalities for TDF nephropathy. Median duration of TDF therapy was 9.5 months, with the earliest case after 2 weeks. Baseline serum creatinine 1.2 mg/dl, increasing to 4.9 after the TDF.

--results:

        --37 cases reported proteinuria by dipstick, 60% of these cases had at least 2+ proteinuria ​(8% 0-trace, 32% 1+) -- note: the dipstick proteinuria primarily measures albuminuria.

        --27 patients had urine protein quantified (either 24-hour collection or spot urine protein-to-creatinine ratio), median proteinuria was 1742 mg/day -- note: this is total protein measured

        --10 of these 27 patients had concomitant urinary albumin measured, with median 236 mg/g creatinine

        --so, the mean urine albumin-to-protein ratio (uAPR) was 0.17

--therefore, TDF nephrotoxicity is predominantly associated with very high urinary protein excretion but not much albuminuria

--there was also a comparison arm of HIV patients undergoing kidney biopsy for other reasons (dx of focal segmental glomerulosclerosis, diabetes, hepatitis C proliferative glomerulonephritis, lupus) and never exposed to TDF had elevations of both proteinuria (2570 mg/gCr) and albuminuria (2029 mg/gCr)

I raise this issue because I think many of us use dipsticks or urinary albumin excretion to assess nephropathy (and appropriately with diabetes, or HIV-associated nephropathy). This study strongly suggests that urinary protein excretion may be a much better marker of nephrotoxicity in those on TDF. So, even though this study looked at patients with pretty advanced nephropathy (median creatinine of 4.9 mg/dl), it does suggest that using a urinary dipstick to detect early TDF nephropathy is probably the wrong thing to do: the uAPR is likely more sensitive (ie, this would support the algorithm: check urinary protein-to-creatinine ratio, and if elevated, then do a uAPR). I would assume that the issues would be the same for other TDF users, such as those on treatment of chronic hepatitis B infection. One hopefully positive change is the likely approval of tenofovir alafenamide, which seems to be as effective clinically as TDF for HIV infection, but has much less nephrotoxicity (eg, see recent findings brought out in the CROI/HIV meeting --  http://betablog.org/croi-2015-tenofovir-alafenamide-new-maturation-inhibitor/ )