Abstract
Sir: Tenofovir disoproxil fumarate (TDF) is generally considered a safe drug, well tolerated by patients and is now recommended as a first-line agent in the backbone of triple agent combination therapy (ART). Since its approval in October 2001 however, there has been a link established between its use and the incidence of proximal renal tubular dysfunction (PRTD) and Fanconi syndrome (Type 2 proximal renal tubular acidosis). 1 Some patients seem to be more vulnerable than others to adverse renal effects such as diabetics, those with hypertensive nephropathy and those also on ritonavir boosted protease inhibitors (PI/r). 2 There are no British HIV Association (BHIVA) guidelines on how best to monitor or manage this problem, although the HIV Medical Association (HIVMA) have given an overview on the investigation types and how often screening for this problem should be performed in patients treated with TDF (namely by biannual monitoring of renal function, serum phosphorous and urine analysis for proteinuria and glycosuria); 3 however, specific advice on when to consider withdrawal of the drug still lacks.
Woodward et al. recently highlighted an important point regarding renal monitoring in TDF-treated patients in a case series of 22 patients referred to a specialist HIV renal clinic with TDF-induced PRTD. They advised the use of urine protein/creatinine ratios (uPCR) as a tool for quantitatively identifying proteinuria. 4 It is worth noting that standard urine dipstick tests advised by the HIVMA are an insensitive method of picking up tubular protein losses (which are of low molecular weight type) such as occurs in those with PRTD due to TDF. To identify tubular protein losses, urine retinal binding protein/creatinine ratio is the required test; however, this is not routinely available outside of research settings. In contrast to the standard urine dipstick test, uPCR acts as a highly sensitive tool in detecting all protein types that may be wasted through the urine, although it will not distinguish between low and high molecular weight types. For patients in whom hypophosphataemia develops, it is worth noting that complications tend to develop in those with sustained phosphate levels of <0.50 mmol/L. 5 At levels above 0.50 mmol/L, current recommendations suggest monitoring and prescribing oral supplementation for short periods; however, for those patients with prolonged and unresolving hypophosphataemia offending drugs should be withdrawn to prevent complications of bone disease. 5
We recently performed a retrospective review of 52 patients who attended our HIV clinic between 1 September and 26 September 2009 and who were on treatment with TDF for a minimum duration of six months (range 6–72 months). All had markers for PRTD checked including renal function, serum phosphorous and 30 had urine dipstick for proteinuria and glycosuria performed. Out of our 52 patients, eight (15.4%) had serum phosphorous of <0.80 mmol/L and 2 (3.8%) had a GFR < 60 mL/minute. None had a serum phosphorous of <0.50 mmol/L. Half of those with biochemical abnormalities were also on a PI/r. Of the 30 patients who had urine analysis performed, five (16.6%) had evidence of proteinuria (with no other identifiable cause for proteinuria) and no patients had glycosuria. When uPCR test was performed on the same group, detection of proteinuria rose to 11 patients (36.6%). None of the patients met the criteria for diagnosis of Fanconi syndrome. Although there was no control group to compare with our cohort, the incidence of hypophosphataemia has been found to be around 10% in ART naive patients and this rises up to around 31% in those treated with ART. 6
In summary, although true Fanconi syndrome appears to be a rare event in those on TDF, biochemical abnormalities and urinary abnormalities associated with its use seem to be common and patients with protein leakage as a result may be picked up earlier with the use of uPCR as a screening tool in these patients. Patients with hypophosphataemia of more than 0.50 mmol/L should be monitored and withdrawal of TDF considered with unresolving biochemical markers of PRTD. The drug should be withdrawn with hypophosphatemia of <0.50 mmol/L. Current BHIVA and HIVMA guidelines should be updated to highlight these points.