tenofovir disoproxil fumarate ( tdf ) , the oral prodrug of tenofovir , is an acyclic nucleotide phosphonate , which is frequently used as a first - line therapy in hiv - infected patients .
it can be conveniently dosed once a day and has a favorable side effect profile , making it one of the most commonly prescribed drugs in this patient population .
the excretion of tdf is primarily through the kidneys . while most of this renal excretion is through filtration , 2030% of tdf
is actively transported in the proximal tubule through organic anion transporter 1 ( oat-1 ) .
initial studies showed tdf to be a safe drug in hiv - infected patients , with a post - marketing survey of 10 343 patients demonstrating renal side effects in only 0.5% of patients .
however , after fda approval , case reports of proximal tubular dysfunction and acute kidney injury emerged [ 5 , 6 ] .
multiple observational cohorts have demonstrated the association of tdf use with a decline in estimated glomerular filtration rate ( egfr ) and development of chronic kidney disease ( ckd ) [ 710 ] .
moreover , tdf use is associated with fanconi syndrome characterized by proximal tubular dysfunction with urinary wasting of phosphate , glucose , amino acids and bicarbonate .
apoptosis of tubular cells and inhibition of mitochondrial dna replication in proximal tubular cells may be involved in the pathogenesis of tdf - induced nephropathy [ 12 , 13 ] .
risk factors for development of tdf - associated nephrotoxicity include polymorphism in genes encoding proximal tubular transporters [ 14 , 15 ] , concomitant use of protease inhibitors [ 1618 ] , preexisting kidney disease , low body mass index , older age , advanced hiv infection , concomitant hepatitis c virus ( hcv ) infection and concurrent use of other nephrotoxic drugs [ 4 , 18 , 20 ] . despite the widely recognized association of tdf with proximal tubular dysfunction ,
the clinical course of patients with tdf - induced proximal tubular dysfunction after discontinuation of tdf remains unclear . in this study
, we describe the characteristics of patients with overt proximal tubular toxicity , with documented urinary phosphate wasting attributed to tdf and their course after the discontinuation of this drug .
we conducted a retrospective observational study of hiv - infected adults evaluated at the johns hopkins nephrology clinic with documented phosphate wasting in the context of tdf use .
we identified 63 patients with presumed tdf toxicity that had discontinued tdf or had adjustment in the tdf dose .
only 15 patients had measurements of urinary phosphate prior to drug discontinuation and were included .
patients who did not have a fractional excretion of phosphate ( fephos ) at the time of presumed tdf toxicity were excluded .
other potential causes of proximal tubule dysfunction , including multiple myeloma , amyloidosis , aminoglycoside exposure or other drug exposures were excluded in all cases
demographic , clinical , laboratory and pharmacologic data were abstracted from electronic medical records at the time of the patients ' initial evaluation in the nephrology clinic .
patients were classified as having diabetes mellitus or hypertension if they had a chart diagnosis of either or were on medications for the treatment of these conditions , respectively .
diagnosis of hepatitis b or hcv infection was based on the presence of antibodies or detectable viral levels by pcr .
fractional excretion of phosphate was calculated by the following equation : urinaryphosphate(up)plasmacreatinine(pcr)plasmaphosphate(pp)urinarycreatinine(ucr)100 
 phosphate wasting was defined as a fephos of > 20% among patients with normal serum phosphate levels ( 2.74.5 mg / dl ) or > 10% among patients with hypophosphatemia ( serum phosphates of < 2.7 mg / dl ) [ 22 , 23 ] .
ratio of renal tubular maximal reabsorption of phosphate to gfr was calculated as follows : tmpgfr=[1{(up
/ pp)(pcr / ucr)}]serumphosphate 
 a tmp / gfr of < 2.6 mg / dl was considered to be low .
hypokalemia was defined as a serum potassium level of < 3.5 meq / l , and low bicarbonate was defined as a bicarbonate level of < 22 meq / l .
estimated gfr was calculated using the chronic kidney disease epidemiology ( ckd - epi ) equation [ 25 , 26 ] .
rapid progression of kidney disease was defined as a fall in gfr of > 5 ml / min/1.73 m per year .
we conducted a retrospective observational study of hiv - infected adults evaluated at the johns hopkins nephrology clinic with documented phosphate wasting in the context of tdf use .
we identified 63 patients with presumed tdf toxicity that had discontinued tdf or had adjustment in the tdf dose .
only 15 patients had measurements of urinary phosphate prior to drug discontinuation and were included .
patients who did not have a fractional excretion of phosphate ( fephos ) at the time of presumed tdf toxicity were excluded .
other potential causes of proximal tubule dysfunction , including multiple myeloma , amyloidosis , aminoglycoside exposure or other drug exposures were excluded in all cases
demographic , clinical , laboratory and pharmacologic data were abstracted from electronic medical records at the time of the patients ' initial evaluation in the nephrology clinic .
patients were classified as having diabetes mellitus or hypertension if they had a chart diagnosis of either or were on medications for the treatment of these conditions , respectively .
diagnosis of hepatitis b or hcv infection was based on the presence of antibodies or detectable viral levels by pcr .
fractional excretion of phosphate was calculated by the following equation : urinaryphosphate(up)plasmacreatinine(pcr)plasmaphosphate(pp)urinarycreatinine(ucr)100 
 phosphate wasting was defined as a fephos of > 20% among patients with normal serum phosphate levels ( 2.74.5 mg / dl ) or > 10% among patients with hypophosphatemia ( serum phosphates of < 2.7 mg / dl ) [ 22 , 23 ] .
ratio of renal tubular maximal reabsorption of phosphate to gfr was calculated as follows : tmpgfr=[1{(up
/ pp)(pcr / ucr)}]serumphosphate 
 a tmp / gfr of < 2.6 mg / dl was considered to be low .
hypokalemia was defined as a serum potassium level of < 3.5 meq / l , and low bicarbonate was defined as a bicarbonate level of < 22 meq / l .
estimated gfr was calculated using the chronic kidney disease epidemiology ( ckd - epi ) equation [ 25 , 26 ] .
rapid progression of kidney disease was defined as a fall in gfr of > 5 ml / min/1.73 m per year .
at the time of diagnosis of tdf toxicity , the mean age of the cohort was 56 years ( range 3876 ) with an sd of 11.3 years as shown in table 1 .
the mean duration of tdf therapy prior to diagnosis of tdf toxicity was 64 months ( sd 21.3 , range 28103 ) .
the mean serum phosphate concentration was 2.3 mg / dl ( range 1.03.6 mg / dl ) , with 11 ( 73% ) patients experiencing hypophosphatemia .
ten patients had vitamin d level checked , and all of them had a 25-oh vitamin d level of > 15 ng / ml ( mean 25-oh vitamin d level 36 ng / ml ) . 

table 1.baseline characteristics of 15 patients with tdf - induced proximal tubulopathy at the time of diagnosischaracteristicsvaluesmean age , years ( range)56 ( 3876)male gender , n ( % ) 12 ( 80)body mass index , kg / m , mean ( sd)23.2 ( 4.0)caucasian , n ( % ) 11 ( 73)hypertension , n ( % ) 9 ( 60)diabetes mellitus , n ( % ) 6 ( 40)hcv infection , n ( % ) 3 ( 20)current smoker , n ( % ) 10 ( 67)duration of tdf use , months mean ( range)64 ( 28103)baseline serum creatinine , mg / dl mean ( sd)(prior to tdf initiation)0.8 ( 0.2)baseline egfr , ml / min/1.73 m mean ( sd ) ( prior to tdf initiation)104 ( 17.0)serum creatinine , mg / dl mean ( sd ) ( at the time of tdf discontinuation)1.22 ( 0.3)egfr , ml / min/1.73 m mean ( sd ) ( at the time of tdf discontinuation)69 ( 19.0)change in egfr from baseline/1.73 m , mean ( sd)35 ( 18.4)serum phosphate , mg / dl mean ( sd)2.3 ( 0.7)serum potassium , mg / dl mean ( sd)3.9 ( 0.6)serum bicarbonate , mg / dl mean ( sd)24.5 ( 3.2)fephos , % , mean ( range)34 ( 2062)tmp / gfr , mean ( range)1.6 ( 0.62.8)glycosuria , n ( % ) 7 ( 46)egfr , estimated gfr ; fephos , fractional excretion of phosphate ; tdf , tenofovir disoproxil fumarate ; tmp , tubular maximal reabsorption of phosphate . baseline characteristics of 15 patients with tdf - induced proximal tubulopathy at the time of diagnosis egfr , estimated gfr ; fephos , fractional excretion of phosphate ; tdf , tenofovir disoproxil fumarate ; tmp , tubular maximal reabsorption of phosphate . despite evidence of phosphate wasting in all the patients , only 53% had concurrent glycosuria . seven ( 47% ) of the 15 patients had > 500 mg / g of protein on a spot urine collection .
eleven ( 73% ) patients had an egfr of > 90 ml / min/1.73 m , and the other four had a gfr of 8090 ml / min/1.73 m , with a mean serum creatinine of 0.8 mg / dl ( range 0.51.0 , sd 0.16 ) .
individual laboratory values of the 15 patients are shown in table 2 . in assessing other features of proximal tubule dysfunction
meq / l , with no bicarbonate < 20 meq / l for the cohort .
similarly , only four patients had concurrent hypokalemia , but all of those who had hypokalemia had potassium of > 3.0
only one patient ( # 2 ) had a normal tmp / gfr in the setting of a high fephos .
he had concurrent glucosuria and a significant drop in his gfr on tdf therapy suggesting renal tubular dysfunction . 

table 2.individual characteristics of 15 patients with proximal tubular dysfunction at the time of diagnosis of tdf - induced proximal tubulopathybaseline serum creatinine ( mg / dl)baseline gfr ( ml / min/1.73 mmonths of tdf therapycreatinine at tdf stop ( mg / dl)gfr at tdf stop ( ml / min/1.73 m)change in gfr ( ml / min/1.73 m)serum phosphate ( mg / dl)fractional excretion of phosphatetmp / gfr ( mg / dl)urine glucoseserum potassium ( meq / l)serum bicarbonate ( meq / l)10.897511.358392.4201.93.12020.71261031.169573.6212.8 + 3.82831.086541.374122.0211.65.02840.8121481.275462.9242.2 + 4.12351.083591.264192.4271.83.33060.8106721.552542.0301.44.22571.088701.552362.0301.44.22580.6122941.270523.1302.24.02690.8103621.077263.1332.1 + 4.428100.6115531.083322.2331.5 + 4.323110.5136561.169671.0420.6 + 3.821120.8100532.130702.2441.13.721130.9111281.185261.0450.6 + 3.322141.081501.263182.6481.44.527151.0921030.5116242.0620.8 + 3.121gfr , estimated glomerular filtration rate ; tdf , tenofovir disoproxil fumarate ; tmp , tubular maximal reabsorption of phosphate.baseline values are those recorded at the time of tdf initiation.patient had an improvement in his gfr after starting of tdf .
individual characteristics of 15 patients with proximal tubular dysfunction at the time of diagnosis of tdf - induced proximal tubulopathy gfr , estimated glomerular filtration rate ; tdf , tenofovir disoproxil fumarate ; tmp , tubular maximal reabsorption of phosphate .
the mean egfr for the 15 patients included at the start of tdf therapy was 104 ml / min/1.73 m ( sd 17.0 , range 81136 ) and decreased to a mean of 69 ml / min/1.73 m ( sd 19.0 , range 30116 ) with a mean egfr decline of 35 ml / min/1.73 m by the time of tdf discontinuation .
only 12 of the 15 patients had multiple egfr measurements before and after discontinuation of tdf at 6-month intervals .
the trend for their gfr based on their point egfr at 6-month intervals and the changes in their egfr at 6-month interval after discontinuation of tdf are shown in figure 1a .
if the patient did not have an egfr measurement at the exact 6-month interval , we used the one which was closest to the 6-month mark within a 2-month interval .
figure 1b depicts the mean egfr of patients in relation to discontinuation of tdf and highlights the slow decline in egfr of patients prior to tdf discontinuation .
one patient ( patient 15 ) in our group had apparent improvement in egfr after initiation of tdf .
however , this may have been due to a decline in this patient 's serum creatinine as a result of poor nutrition and muscle atrophy prior to the patient 's death , which occurred within a month of tdf discontinuation , rather than an actual improvement in renal function ; his weight decreased from 76 to 62 kg in the 4 months prior to discontinuation of the tdf . 

1.(a ) trends of egfr values 48 months prior or 24 months after discontinuation of tdf in 12 patients .
( a ) trends of egfr values 48 months prior or 24 months after discontinuation of tdf in 12 patients .
concomitant antiretroviral use included 11 patients on ritonavir boosted protease inhibitors ( 5 atazanavir ) , 8 patients on efavirenz and 4 on raltegravir . all patients discontinued tenofovir .
new regimens included addition of the protease inhibitor darunavir with ritonavir in 2 patients ( in addition to the 11 already on a boosted protease inhibitor ) , raltegravir in 6 and abacavir in 5 .
of these , six had normalization of their fephos between 8 and 60 weeks after tdf discontinuation .
three others had a decrease in their fephos by the time of their last measurement between 8 and 52 weeks after drug discontinuation .
all three of these had been hypophosphatemic at the time of drug discontinuation and had normalized their serum phosphate levels .
one patient had an increase in fephos measured 2 months after tdf discontinuation . at that time
the serum phosphate had increased from 2.0 to 2.3 mg / dl ( patient 3 ) ; no further assessments were performed . of the eleven ( 73% ) hypophosphatemic patients , all patients , except one , had normalization of serum phosphate levels after discontinuation of tdf .
the one patient ( # 3 ) without normalization of his serum phosphate level had an increase from 2.0 to 2.3 after 2 months without further follow - up .
of the four patients who had a normal serum phosphate at the time diagnosis , three patients had an increase in their serum phosphate after discontinuation of tdf . of note , in at least three hypophosphatemic patients it took > 6 months before their serum phosphate normalized . all patients with urine glucose had resolution of glycosuria .
one patient ( # 10 ) had persistent glycosuria a year after stopping the tdf .
though the fephos was not reassessed , the serum phosphate had normalized in this patient and has been in the normal range for over 2.5 years since stopping tdf .
twelve ( 86% ) of 14 with loss of kidney function on tdf had an increase in egfr after discontinuation of tdf .
the egfr started to increase in these patients within 6 months and continued to improve beyond 6 months before stabilizing ( figure 1a , b ) .
one patient , who had an improvement in egfr after discontinuation of tdf , later had a decline in his egfr after 2 years as a result of biopsy - proven diabetic nephropathy .
two of the 14 patients continued to experience a decline in egfr despite discontinuation of tdf .
one had an underlying ckd with ongoing illicit drug use and history of non - adherence .
the other had only 6 months of follow - up , and this failure to recover egfr might be explained by a residual effect from tdf use .
at the time of diagnosis of tdf toxicity , the mean age of the cohort was 56 years ( range 3876 ) with an sd of 11.3 years as shown in table 1 .
the mean duration of tdf therapy prior to diagnosis of tdf toxicity was 64 months ( sd 21.3 , range 28103 ) .
the mean serum phosphate concentration was 2.3 mg / dl ( range 1.03.6 mg / dl ) , with 11 ( 73% ) patients experiencing hypophosphatemia .
ten patients had vitamin d level checked , and all of them had a 25-oh vitamin d level of > 15 ng / ml ( mean 25-oh vitamin d level 36 ng / ml ) . 

table 1.baseline characteristics of 15 patients with tdf - induced proximal tubulopathy at the time of diagnosischaracteristicsvaluesmean age , years ( range)56 ( 3876)male gender , n ( % ) 12 ( 80)body mass index , kg / m , mean ( sd)23.2 ( 4.0)caucasian , n ( % ) 11 ( 73)hypertension , n ( % ) 9 ( 60)diabetes mellitus , n ( % ) 6 ( 40)hcv infection , n ( % ) 3 ( 20)current smoker , n ( % ) 10 ( 67)duration of tdf use , months mean ( range)64 ( 28103)baseline serum creatinine , mg / dl mean ( sd)(prior to tdf initiation)0.8 ( 0.2)baseline egfr , ml / min/1.73 m mean ( sd ) ( prior to tdf initiation)104 ( 17.0)serum creatinine , mg / dl mean ( sd ) ( at the time of tdf discontinuation)1.22 ( 0.3)egfr , ml / min/1.73 m mean ( sd ) ( at the time of tdf discontinuation)69 ( 19.0)change in egfr from baseline/1.73 m , mean ( sd)35 ( 18.4)serum phosphate , mg / dl mean ( sd)2.3 ( 0.7)serum potassium , mg / dl mean ( sd)3.9 ( 0.6)serum bicarbonate , mg / dl mean ( sd)24.5 ( 3.2)fephos , % , mean ( range)34 ( 2062)tmp / gfr , mean ( range)1.6 ( 0.62.8)glycosuria , n ( % ) 7 ( 46)egfr , estimated gfr ; fephos , fractional excretion of phosphate ; tdf , tenofovir disoproxil fumarate ; tmp , tubular maximal reabsorption of phosphate . baseline characteristics of 15 patients with tdf - induced proximal tubulopathy at the time of diagnosis egfr , estimated gfr ; fephos , fractional excretion of phosphate ; tdf , tenofovir disoproxil fumarate ; tmp , tubular maximal reabsorption of phosphate . despite evidence of phosphate wasting in all the patients , only 53% had concurrent glycosuria . seven ( 47% ) of the 15 patients had > 500 mg / g of protein on a spot urine collection .
eleven ( 73% ) patients had an egfr of > 90 ml / min/1.73 m , and the other four had a gfr of 8090 ml / min/1.73 m , with a mean serum creatinine of 0.8 mg / dl ( range 0.51.0 , sd 0.16 ) .
individual laboratory values of the 15 patients are shown in table 2 . in assessing other features of proximal tubule dysfunction
meq / l , with no bicarbonate < 20 meq / l for the cohort .
similarly , only four patients had concurrent hypokalemia , but all of those who had hypokalemia had potassium of > 3.0
only one patient ( # 2 ) had a normal tmp / gfr in the setting of a high fephos .
he had concurrent glucosuria and a significant drop in his gfr on tdf therapy suggesting renal tubular dysfunction . 

table 2.individual characteristics of 15 patients with proximal tubular dysfunction at the time of diagnosis of tdf - induced proximal tubulopathybaseline serum creatinine ( mg / dl)baseline gfr ( ml / min/1.73 mmonths of tdf therapycreatinine at tdf stop ( mg / dl)gfr at tdf stop ( ml / min/1.73 m)change in gfr ( ml / min/1.73 m)serum phosphate ( mg / dl)fractional excretion of phosphatetmp / gfr ( mg / dl)urine glucoseserum potassium ( meq / l)serum bicarbonate ( meq / l)10.897511.358392.4201.93.12020.71261031.169573.6212.8 + 3.82831.086541.374122.0211.65.02840.8121481.275462.9242.2 + 4.12351.083591.264192.4271.83.33060.8106721.552542.0301.44.22571.088701.552362.0301.44.22580.6122941.270523.1302.24.02690.8103621.077263.1332.1 + 4.428100.6115531.083322.2331.5 + 4.323110.5136561.169671.0420.6 + 3.821120.8100532.130702.2441.13.721130.9111281.185261.0450.6 + 3.322141.081501.263182.6481.44.527151.0921030.5116242.0620.8 + 3.121gfr , estimated glomerular filtration rate ; tdf , tenofovir disoproxil fumarate ; tmp , tubular maximal reabsorption of phosphate.baseline values are those recorded at the time of tdf initiation.patient had an improvement in his gfr after starting of tdf .
individual characteristics of 15 patients with proximal tubular dysfunction at the time of diagnosis of tdf - induced proximal tubulopathy gfr , estimated glomerular filtration rate ; tdf , tenofovir disoproxil fumarate ; tmp , tubular maximal reabsorption of phosphate .
the mean egfr for the 15 patients included at the start of tdf therapy was 104 ml / min/1.73 m ( sd 17.0 , range 81136 ) and decreased to a mean of 69 ml / min/1.73 m ( sd 19.0 , range 30116 ) with a mean egfr decline of 35 ml / min/1.73 m by the time of tdf discontinuation .
only 12 of the 15 patients had multiple egfr measurements before and after discontinuation of tdf at 6-month intervals .
the trend for their gfr based on their point egfr at 6-month intervals and the changes in their egfr at 6-month interval after discontinuation of tdf are shown in figure 1a .
if the patient did not have an egfr measurement at the exact 6-month interval , we used the one which was closest to the 6-month mark within a 2-month interval .
figure 1b depicts the mean egfr of patients in relation to discontinuation of tdf and highlights the slow decline in egfr of patients prior to tdf discontinuation .
one patient ( patient 15 ) in our group had apparent improvement in egfr after initiation of tdf .
however , this may have been due to a decline in this patient 's serum creatinine as a result of poor nutrition and muscle atrophy prior to the patient 's death , which occurred within a month of tdf discontinuation , rather than an actual improvement in renal function ; his weight decreased from 76 to 62 kg in the 4 months prior to discontinuation of the tdf . 

1.(a ) trends of egfr values 48 months prior or 24 months after discontinuation of tdf in 12 patients .
( a ) trends of egfr values 48 months prior or 24 months after discontinuation of tdf in 12 patients .
concomitant antiretroviral use included 11 patients on ritonavir boosted protease inhibitors ( 5 atazanavir ) , 8 patients on efavirenz and 4 on raltegravir .
all patients discontinued tenofovir . new regimens included addition of the protease inhibitor darunavir with ritonavir in 2 patients ( in addition to the 11 already on a boosted protease inhibitor ) , raltegravir in 6 and abacavir in 5 .
of these , six had normalization of their fephos between 8 and 60 weeks after tdf discontinuation .
three others had a decrease in their fephos by the time of their last measurement between 8 and 52 weeks after drug discontinuation .
all three of these had been hypophosphatemic at the time of drug discontinuation and had normalized their serum phosphate levels .
one patient had an increase in fephos measured 2 months after tdf discontinuation . at that time
the serum phosphate had increased from 2.0 to 2.3 mg / dl ( patient 3 ) ; no further assessments were performed .
of the eleven ( 73% ) hypophosphatemic patients , all patients , except one , had normalization of serum phosphate levels after discontinuation of tdf .
the one patient ( # 3 ) without normalization of his serum phosphate level had an increase from 2.0 to 2.3 after 2 months without further follow - up .
of the four patients who had a normal serum phosphate at the time diagnosis , three patients had an increase in their serum phosphate after discontinuation of tdf . of note , in at least three hypophosphatemic patients it took > 6 months before their serum phosphate normalized . all patients with urine glucose
one patient ( # 10 ) had persistent glycosuria a year after stopping the tdf .
though the fephos was not reassessed , the serum phosphate had normalized in this patient and has been in the normal range for over 2.5 years since stopping tdf .
twelve ( 86% ) of 14 with loss of kidney function on tdf had an increase in egfr after discontinuation of tdf .
the egfr started to increase in these patients within 6 months and continued to improve beyond 6 months before stabilizing ( figure 1a , b ) .
one patient , who had an improvement in egfr after discontinuation of tdf , later had a decline in his egfr after 2 years as a result of biopsy - proven diabetic nephropathy .
two of the 14 patients continued to experience a decline in egfr despite discontinuation of tdf .
one had an underlying ckd with ongoing illicit drug use and history of non - adherence .
the other had only 6 months of follow - up , and this failure to recover egfr might be explained by a residual effect from tdf use .
the potential of tdf to cause nephrotoxicity reflected by increased serum creatinine is well described in the literature [ 28 , 29 ] . furthermore , scherzer et al . in a large cohort study demonstrated that each year of tdf exposure was associated with a 33% increased risk ckd .
however , serum creatinine is a late marker of kidney dysfunction , and urinary phosphate wasting reflective of proximal tubular dysfunction may be a more sensitive marker for tdf - induced kidney injury .
the frequency of tubulopathy reported in observational and clinical cohorts may be underestimated since most trials did not perform specific detailed analysis for the diagnosis of phosphate wasting [ 3133 ] .
the current study demonstrates that in a series of patients with tenofovir nephrotoxicity as reflected by urine phosphate wasting the diagnosis is often late in the treatment course ( average of 64 months after tdf initiation ) and occurs in those who have normal kidney function at baseline .
moreover , it is usually associated with hypophosphatemia though not infrequently the serum phosphate can be normal with renal phosphate wasting .
this is generally not associated with other components of fanconi syndrome such as hypokalemia and metabolic acidosis .
glycosuria was present in only 47 percent of patients and therefore appears to be a less sensitive marker than both serum phosphate and urine phosphate wasting .
though declining egfr ( increasing serum creatinine ) was occurring slowly over time prior to the diagnosis of toxicity , this may not have been clinically recognized due to the very gradual absolute increase in serum creatinine over years .
importantly , this study suggests that vigilance for tenofovir toxicity should remain beyond the early years of treatment .
in addition , since no patient showed full recovery of egfr , earlier identification of toxicity prior to development of renal function decline is important . certainly , close monitoring of egfr over time , rather than serum creatinine alone ( with clear documentation of a baseline level ) might detect subtle decline and alert one earlier to the possibility of nephrotoxicity .
in addition , only 5 of 15 patients had serum creatinine levels beyond the  normal range of 0.51.2 mg / dl at the time of diagnosis of nephrotoxicity .
this likely also explains the significant declines in egfr prior to detection and further emphasizes the need to use gfr estimation in the monitoring of kidney function .
the difficulty of detecting tdf nephrotoxicity in the context of subtle changes in serum creatinine further highlights the importance of monitoring phosphate excretion , serum phosphate , urinary protein and glycosuria for tdf toxicity rather than relying on serum creatinine as a lone marker of kidney injury .
earlier detection of urinary phosphate wasting or serum phosphate decline may have identified nephrotoxicity sooner .
however , urine phosphate was not previously assessed in any patient , and serum phosphate levels were not monitored in the majority of the patients .
current guidelines by the infectious disease society of america recommend monitoring of serum creatinine , serum phosphate , glycosuria and proteinuria twice a year in patients who are prescribed tdf and have an egfr of < 90 ml / min/1.73 m or in patients with diabetes and hypertension who have a high risk of kidney disease .
despite these guidelines , only 7 ( 47% ) of the 15 patients in this series had a serum phosphate level checked prior to their referral to the renal clinic even after years of tdf therapy .
also , since not all patients developed hypophosphatemia , the diagnosis of tdf - induced tubulopathy would have been missed based on current screening guidelines in 27% of patients who had renal phosphate wasting with normal serum phosphate levels . as noted earlier , the average time for the detection of proximal tubular dysfunction after start of tdf therapy in our cohort was 64 months , a duration that is much longer than has been previously reported in other studies .
this underscores the necessity of continued monitoring of side effects in patients even if they have tolerated tdf therapy for years . even after discontinuation of tdf , recovery of serum phosphate and improvement of egfr
, none of the patients returned to their baseline egfr after a mean follow - up of 23 months after discontinuation of tdf .
as noted earlier , the implications may be important with regard to earlier identification of tdf toxicity , as ckd is associated with a long - term increase in morbidity and mortality in hiv - infected patients [ 37 , 38 ] .
the apparent loss of kidney function , seen here and in earlier studies , despite drug discontinuation , would support monitoring potentially more sensitive markers of toxicity such as serum phosphate and fephos .
it is notable that the majority of patients were on a boosted protease inhibitor at the time of development of the proximal tubular dysfunction .
several studies have suggested increased toxicity of tenofovir due to the effects of protease inhibitors , particularly ritonavir , on apical membrane transporters involved in the elimination of tenofovir from the proximal tubular cell .
decreased elimination has been proposed to increase intracellular concentrations of the drug and hence increase toxicity .
however , since no control group is assessed , it is difficult to determine the role in protease inhibitor use in this cohort .
moreover , patients who are referred to the nephrology clinic are more likely to have severe kidney disease .
the retrospective nature of the study had its inherent limitations in terms of selection bias and missing data .
it is also important to note that urine phosphate measurements were not obtained on a fasting urine sample , which may make measurements less reliable .
finally , most of our patients had no urinary phosphate measurements at preset intervals of follow - up .
tdf - induced phosphate wasting may be a more sensitive marker for kidney dysfunction than an increased serum creatinine level .
moreover , tubular dysfunction may only become evident after years of tdf therapy , even in those who have normal kidney function at the time of starting tdf ; this emphasizes the importance of continued monitoring in all patients treated with tdf .
 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 3876 ) . 
 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 2062 ) . 
 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 . 
Introduction
Methods
Study design and population
Data collection
Definitions
Results
Baseline characteristics
Effects of discontinuation of TDF
Discussion
Conclusion
Conflict of interest statement