American Journal of Kidney Diseases
Volume 54, Issue 6 , Pages 1034-1042, December 2009

Subclinical Tubular Injury in HIV-Infected Individuals on Antiretroviral Therapy: A Cross-sectional Analysis

  • Andrew M. Hall, MD, MRCP

      Affiliations

    • Department of Cell and Developmental Biology, University College of London, London, UK
    • Centre for Nephrology, University College London, London, London, UK
    • Corresponding Author InformationAddress correspondence to Andrew M. Hall, MD, MRCP, Department of Cell and Developmental Biology, UCL, Gower St, London WC1E 6BT, UK
    • ,
  • Simon G. Edwards, MD, FRCP

      Affiliations

    • The Mortimer Market Centre, Camden Primary Care Trust, London, London, UK
    • ,
  • Marta Lapsley, MD, FRCPath

      Affiliations

    • South West Thames Institute for Renal Research, Epsom and St. Helier University Hospitals National Health Service Trust, Carshalton, London, UK
    • ,
  • John O. Connolly, MD, PhD, FRCP

      Affiliations

    • Centre for Nephrology, University College London, London, London, UK
    • ,
  • Kreesan Chetty, RGN

      Affiliations

    • The Mortimer Market Centre, Camden Primary Care Trust, London, London, UK
    • ,
  • Stephen O'Farrell, RGN

      Affiliations

    • The Mortimer Market Centre, Camden Primary Care Trust, London, London, UK
    • ,
  • Robert J. Unwin, MD, PhD, FRCP

      Affiliations

    • Centre for Nephrology, University College London, London, London, UK
    • ,
  • Ian G. Williams, MD, FRCP

      Affiliations

    • The Mortimer Market Centre, Camden Primary Care Trust, London, London, UK
    • Centre for Sexual Health and HIV Research, University College London, London, UK

Received 17 March 2009; accepted 8 July 2009. published online 24 September 2009.

Article Outline

Background

Randomized control studies have not shown an association between treatment with tenofovir (TDF) and clinically significant kidney toxicity. However, multiple cases of renal tubular toxicity have been described in patients with HIV treated with TDF. It is unclear whether spot urine protein- or albumin-creatinine ratio is a sufficiently sensitive screening test to detect subclinical renal tubular toxicity in patients with HIV.

Study Design

Cross-sectional.

Setting & Participants

99 patients with HIV with serum creatinine levels < 1.70 mg/dL and dipstick-negative proteinuria; 19 were antiretroviral treatment (ART) naive, 47 were on a TDF regimen, and 33 were on ART, but with no history of TDF exposure.

Predictor or Factor

Exposure to TDF.

Outcomes

Spot urine concentrations of retinol-binding protein (RBP; a low-molecular-weight protein normally reabsorbed by the proximal tubule), N-acetyl-β-d-glucosaminidase (NAG; a proximal tubule lysosomal enzyme), albumin (A; a marker of glomerular disease), and protein (P; a standard clinical screening test for kidney pathological states) expressed as a ratio to creatinine (C; URBP/C, UNAG/C, UA/C, and UP/C, respectively).

Results

There were no significant differences in median UA/C (ART-naive, 7.3 mg/g [range, 0-245.8 mg/g]; TDF, 9.0 mg/g [range, 0.1-184.1 mg/g]; and non-TDF, 10.5 mg/g [range, 2.6-261.6 mg/g]; P = 0.8). URBP/C excretion was significantly higher in the TDF group (median, 214.2 μg/g [range, 26.8-17,454.5 μg/g]) than in the ART-naive group (92.5 μg/g [range, 21.3-3,969.0 μg/g]; P = 0.03); there was also a trend toward higher values than in the non-TDF group (111.6 μg/g [range, 31.0-6,136.3 μg/g]; P = 0.08). UNAG/C excretion was significantly higher in both the TDF (median, 394.7 μmol/h/g [range, 140.5-10,851.3 μmol/h/g]; P = 0.01) and non-TDF (406.8 μmol/h/g [range, 12.4-8,485.8 μmol/h/g]; P = 0.03) groups compared with the ART-naive group (218.6 μmol/h/g [range, 56.5-2,876.1 μmol/h/g]). UP/C was significantly higher in the TDF (median, 123.9 mg/g [range, 53.1-566.4 mg/g]) than the non-TDF group (97.3 mg/g [range, 0-451.3 mg/g]; P = 0.03). The proportion of patients with evidence of tubular dysfunction (increased URBP/C and/or UNAG/C) was considerably higher than the proportion with an increase in UA/C or UP/C in all groups: for ART-naive, 52.6% vs 31.6% vs 25.0%; for TDF, 80.9% vs 29.8% vs 52.2%; and for non-TDF, 81.8% vs 39.4% vs 30.0%. The level of agreement among the different urinary test results was low.

Limitations

Causality cannot be established from single measurements of urinary markers in a cross-sectional study.

Conclusions

Patients with HIV had high rates of subclinical proteinuria, but neither UP/C nor UA/C is sufficiently sensitive alone to detect many of these cases. Patients using TDF have increased URBP/C and UP/C; the significance of this will need to be determined from longer-term outcome studies.

Index Words: HIV, renal tubule, antiretroviral therapy, tenofovir, proteinuria

 

As survival in HIV patients improves with the development of more effective antiretroviral therapy (ART), the balance of kidney disease attributed to HIV is changing from direct pathological effects of the virus (HIV-associated nephropathy and immune-complex nephropathy) to ART-related renal toxicity.1, 2 Therefore, it is becoming increasingly important that the burden and nature of ART-related kidney disease are defined and understood. Tenofovir (TDF) is a widely used and effective antiretroviral drug. Although randomized control studies have not shown an association between treatment with TDF and clinically significant kidney toxicity,3, 4, 5 numerous case reports of renal tubular toxicity in patients using TDF have begun to emerge in the literature.6, 7, 8, 9 In many cases, patients developed the renal Fanconi syndrome, which results from dysfunction of the proximal tubule. Fanconi syndrome is characterized by phosphaturia and hypophosphatemia, nondiabetic glycosuria, renal tubular acidosis, and low-molecular-weight proteinuria,10 and has been linked to toxicity from a number of drugs, including ART.11

Most of the original TDF studies that screened for renal dysfunction measured only serum creatinine (and estimated glomerular filtration rate [eGFR]) and urine dipstick proteinuria (mainly albuminuria), which together are primarily markers of glomerular disease and will not necessarily detect tubular disease, especially when mild. Tubular proteinuria, which consists of low-molecular-weight proteins such as retinol-binding protein (RBP) and enzymes such as N-acetyl-β-d-glucosaminidase (NAG), is a more sensitive and reliable marker of early proximal tubule dysfunction.12 RBP is relatively freely filtered by the glomerulus and almost completely reabsorbed along the proximal tubule; its presence in urine in increased amounts usually indicates defective proximal tubular uptake and/or transport.13 NAG, which is not delivered, but is derived from proximal tubular cells, is a sensitive index of proximal tubule damage when levels are increased in urine.14 Their concentrations can be compared using a urinary marker of glomerular disease, such as albumin.12 Urine concentrations of RBP, NAG, and albumin (A) are normally expressed as a ratio to creatinine (C; URBP/C, UNAG/C, and UA/C, respectively) to account for variations in urine concentrations among individuals. Urine protein-creatinine ratio (UP/C) is an established clinical screening tool for nephropathy and correlates well with 24-hour total urinary protein excretion15; however, it is not clear how sensitive it is in detecting tubular disease. Recently, The National Institute for Clinical Excellence (NICE) in the United Kingdom has advocated use of UA/C as a screening tool for chronic kidney disease (www.nice.org.uk/Guidance/CG73), because it is well standardized among laboratories and is less expensive to perform than UP/C. However, this may not detect subclinical renal tubular disease.

We have screened the urine of patients with HIV without overt kidney disease to investigate: (1) the prevalence of subclinical renal tubular disease, (2) whether patients using TDF are at increased risk of tubular proteinuria, and (3) whether UP/C or UA/C is sufficiently sensitive to detect these cases.

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Methods 

Study Groups 

Ninety-nine adult patients with serum creatinine levels < 1.70 mg/dL and dipstick-negative proteinuria were recruited from an HIV outpatient clinic: 19 were ART naive and 80 were stable on ART. Of these, 47 were following a regimen containing TDF and 33 were on an ART regimen without TDF (non-TDF) and had not received TDF in the past. Patients in both treatment groups were stable on their current ART regimen for > 6 months and had an HIV RNA level < 50 copies/mL for at least 3 months before study entry (although not necessarily < 50 copies/mL at the time of recruitment). None had viral hepatitis B or C or diabetes (which tends to cause increases in urinary NAG levels16). Patients with a history of renal disease were excluded.

Urinary Assays 

Random spot urine samples obtained during clinic visits were frozen within 4 hours of collection and stored at −80°C. URBP/C, UNAG/C, UA/C, and UP/C subsequently were measured. Urinary RBP was measured using a sandwich microtiter plate enzyme immunoassay with polyclonal antibodies from Dako Ltd (Glostrup, Denmark); the second antibody was labeled with horseradish peroxidase. Reference ranges for the healthy adult population have been established previously.17 Urinary NAG was measured using a kit from PPR Diagnostics Ltd (London, UK) with a microtiter plate format direct assay of enzyme activity and using 2-methoxy-4-(2-nitrovinyl) phenyl-glucosaminide as substrate. The reference range used was that given by the manufacturer. Urinary albumin was measured on a Siemens Advia 2400 Chemistry System (Siemens Healthcare, Camberley, UK) using an immunoturbidimetric (antibody reaction) method, with reagents from Olympus Ltd (Watford, UK). Urinary creatinine also was measured on a Siemens Advia 2400 using a modified Jaffé reaction. Urinary protein was measured using a Roche Integra 800 analyzer (Roche Diagnostics UK, Burgess Hill, UK).

Clinical Data 

Data for demographics, drug and medical history, and routine laboratory test results were collected from review of clinic notes and clinic databases; eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) Study equation (4-variable isotope-dilution mass spectrometry traceable).18

Statistical Analysis 

One-way analysis of variance (for parametric data) or Kruskal-Wallis test (for nonparametric data) was used to investigate statistical differences among study groups. When differences were found, individual groups were compared with each other using an unpaired t test (for parametric data) or unpaired Mann-Whitney test (for nonparametric data) with Bonferroni correction. The relationship between variables was explored using Spearman correlation coefficient (rs). P < 0.05 was considered significant (all P > 0.9 are expressed as 0.9). Agreement between different urinary tests in defining abnormal proteinuria was measured using κ test (0, no agreement to 1, perfect agreement).

Ethical Approval 

The study was approved by the National Hospital for Neurology and Neurosurgery Regional Ethics Committee. All patients provided written informed consent.

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Results 

Patient Characteristics 

Table 1 lists baseline demographics, ART history, and laboratory blood test results, along with data for prevalence of hypertension and potentially nephrotoxic non-HIV therapy in each study group. The 3 groups were well matched for sex and ethnicity. As expected, patients in the ART-naive group were slightly younger and had higher plasma HIV RNA levels compared with the 2 treatment groups. Of patients on ART, 94% (44 of 47 in the TDF group and 31 of 33 in the non-TDF group) had plasma HIV RNA levels < 50 copies/mL at the time of recruitment; only 1 patient had an HIV RNA level > 400 copies/mL. There was no significant difference in CD4 counts (P = 0.3) between study groups. The non-TDF group had received ART for a longer median time than the TDF group, although both groups had been treated with a similar median total number of ART drugs.

Table 1. Demographics, Drug History, and Routine Laboratory Values
ART-Naive (n = 19)TDF Exposed (n = 47)No TDF Exposure (n = 33)P
Age (y)36(26-47)43(27-69)43(29-65)ANOVA, <0.05; TDF vs non-TDF, 0.9
Men95(18)91(43)91(30)0.2
Ethnicity: white68(13)83(39)82(27)0.2
Time on ART (mo)—44(5-146)86(6-137)0.04
Time on TDF therapy (mo)—32(3-68)——
Proportion on protease inhibitor—47(22)33(11)0.2
Total number of ART drugs ever received—5(3-10)4(3-9)0.1
Proportion exposed to ≥ 2 classes of ART—72(34)70(23)0.2
Proportion on a nephrotoxic drug21(4)17(8)27(9)0.2
Proportion on NSAIDs5(1)0(0)3(1)0.2
Proportion on acyclovir16(3)9(4)3(1)0.2
Proportion on ACEi/Ang II blocker0(0)4(2)6(2)0.2
Proportion on statin0(0)9(4)15(5)0.1
Proportion on valproate0(0)0(0)3(1)0.2
Hypertension5(1)9(4)15(5)0.2
CD4 count (× 106/L)370(20-860)420(120-1,140)440(200-1,060)0.3
Viral load (copies/mL)14,300(600-430,000)<50(<50-80)<50(<50-4,600)ANOVA, <0.01; TDF vs non-TDF, 0.9
eGFR (mL/min/1.73 m2)100(64-159)99(53-147)98(62-131)0.9

Note: Values given as median (range) or percentage (number).

Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; Ang II, angiotensin II; ANOVA, analysis of variance; ART, antiretroviral therapy; eGFR, estimated glomerular filtration rate; NSAID, nonsteroidal anti-inflammatory drug; TDF, tenofovir.

eGFR and Serum Phosphate 

Median eGFR was > 90 mL/min/1.73 m2 in all 3 study groups, and there were no significant differences among groups (P = 0.9). Only 1 patient in the study (in the TDF group) had an eGFR < 60 mL/min/1.73 m2. Median serum phosphate level was lower in the TDF group (2.91 mg/dL [range, 1.42-4.43 mg/dL]) than in either the ART-naive (3.07 mg/dL [range, 2.42-3.65 mg/dL]) or non-TDF (3.21 mg/dL [range, 1.80-4.21 mg/dL]) groups (Fig 1). However, these differences were not statistically significant (P = 0.2). The proportion of patients with phosphate values less than the normal range (<2.48 mg/dL) was greater in the TDF group (11 of 43 [25.6%]) than either the ART-naive (1 of 17 [5.9%]) or non-TDF (3 of 32 [9.4%]) groups; however, these differences were not statistically significant (P > 0.2).

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  • Figure 1. 

    Serum phosphate levels and hypoposphatemia in the study groups. (A) There were no significant differences among groups in serum phosphate values. Values given as mean (point), median (solid line), 25th and 75th percentiles (box), range (crosses), and 5th and 95th percentiles (error bars). The dashed line represents the lower limit of the normal adult range (< 2.48 mg/dL). (B) The proportion of patients in the group exposed to tenofovir (TDF group) who had a serum phosphate value less than the normal range was greater than in the antiretroviral treatment (ART)-naive group and those with no exposure to tenofovir (non-TDF group), but this difference was not statistically significant. Conversion factor for serum phosphate in mg/dL to mmol/L, ×0.3229.

Urinary Markers 

Values for urinary markers in the 3 study groups are listed in Table 2. URBP/C was significantly different among study groups (P = 0.01). It was higher in the TDF group than in the ART-naive group (P = 0.03), and there also was a trend toward it being higher than in the non-TDF group (P = 0.08; Fig 2A). Within the TDF group, there was no significant difference in URBP/C between patients using a protease inhibitor and those who were not (P = 0.6). Furthermore, there was no significant correlation between time on TDF therapy and URBP/C (rs = 0.12; P = 0.4).

Table 2. Urinary Markers in Patients With HIV
ART-Naive (n = 19)TDF (n = 47)Non-TDF (n = 33)P
URBP/C (μg/g C)92.5(21.3-3969.0)214.2(26.8-17454.5)111.6(31.0-6,136.3)ART-naive vs TDF, 0.03; ART-naive vs non-TDF, 0.9; TDF vs non-TDF, 0.08
UNAG/C (μmol/h/g C)218.6(56.5-2,876.1)394.7(140.5-10,851.3)406.8(12.4-8,485.8)ART-naive vs TDF, 0.01; ART-naive vs non-TDF, 0.03; TDF vs non-TDF, 0.9
UA/C (mg/g C)7.3(0-245.8)9.0(0.1-184.1)10.5(2.6-261.6)ART-naive vs TDF, 0.9; ART-naive vs non-TDF, 0.9; TDF vs non-TDF, 0.9
UP/C (mg/g C)92.9(0-336.3)123.9(53.1-566.4)97.3(0-451.3)ART-naive vs TDF, 0.06; ART-naive vs non-TDF, 0.9; TDF vs non-TDF, 0.03

Note: Values given as median (range) and expressed as a ratio to urinary creatinine. Conversion factor for a urinary value expressed per gram of creatinine to a value per millimoles of creatinine, ×0.113.

Abbreviations and definitions: ART, antiretroviral treatment; C, creatinine; non-TDF, no exposure to tenofovir; TDF, exposed to tenofovir; UA/C, urinary albumin-creatinine ratio; UNAG/C, urinary N-acetyl-β-d-glucosaminidase–creatinine ratio; UP/C, urinary protein-creatinine ratio; URBP/C, urinary retinol-binding protein–creatinine ratio.

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  • Figure 2. 

    Urinary markers. (A) Urinary retinol-binding protein (RBP)-creatinine (creat) ratio (normal range, < 159 μg/g]) was higher in the group exposed to tenofovir (TDF group) than either the antiretroviral treatment (ART)-naive group or those with no exposure to tenofovir (non-TDF group). (B) Urinary N-acetyl-β-d-glucosaminidase (NAG)-creat ratio (normal range, < 248 μmol/h/g) was higher in both the TDF and non-TDF treatment groups compared with the ART-naive group. (C) Urinary albumin-creat ratio (normal range, < 22 mg/g) did not differ significantly among the study groups. (D) Urinary protein-creat ratio (normal range, < 115 mg/g) was greater in the TDF group than either the ART-naive or non-TDF group. Values given are mean (point), median (solid line), 25th and 75th percentiles (box), range (crosses), and 5th and 95th percentiles (error bars). Dashed lines represent the upper limits of the normal range. Conversion factor for a urinary value expressed per gram of creatinine to a value per millimoles of creatinine, ×0.113.

UNAG/C also was significantly different among groups (P = 0.01). It was higher in the TDF group than in the ART-naive group (P = 0.01), but not the non-TDF group (P = 0.9). The non-TDF group also had significantly higher UNAG/C values than the ART-naive group (P = 0.03; Fig 2B). There was no significant correlation between time on ART therapy and UNAG/C (rs = 0.17; P = 0.1).

There were no significant differences among study groups in UA/C (P = 0.8; Fig 2C). However, UP/C was significantly different among groups (P = 0.01), with a trend toward a higher value in the TDF group than in the ART-naive group (P = 0.06). UP/C was significantly higher in the TDF group than the non-TDF group (P = 0.03; Fig 2D). There was no significant difference in UP/C between the non-TDF and ART-naive groups (P = 0.9). These results indicate that patients exposed to TDF have increased proteinuria.

The strongest correlation between urinary markers was found between URBP/C and UNAG/C, followed by (in descending order of association) UNAG/C and UA/C, URBP/C and UA/C, URBP/C and UP/C, UNAG/C and UP/C, and UA/C and UP/C (Table 3). Scatter plots comparing UA/C (the NICE-recommended screening tool) with URBP/C, UNAG/c, and UP/C are shown (Fig 3) for each of the 3 study groups. Although there appeared to be some degree of correlation among urinary markers, the level of agreement between each test in detecting abnormal proteinuria (defined as greater than the normal range) was low (Table 4). This suggests that each test measures different aspects of renal dysfunction in patients with HIV.

Table 3. Correlation Between Urinary Markers
URBP/CUNAG/CUA/CUP/C
URBP/C—0.60(P=0.01)0.53(P=0.01)0.33(P=0.01)
UNAG/C0.60(P=0.01)—0.56(P=0.01)0.26(P=0.02)
UA/C0.53(P=0.01)0.56(P=0.01)—0.20(P=0.05)
UP/C0.33(P=0.01)0.26(P=0.01)0.20(P=0.05)—

Note: Values given as Spearman coefficients (range, −1 to +1) and relevant P values.

Abbreviations: UA/C, urinary albumin-creatinine ratio; UNAG/C, urinary N-acetyl-β-d-glucosaminidase–creatinine ratio; UP/C, urinary protein-creatinine ratio; URBP/C, urinary retinol-binding protein–creatinine ratio.

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  • Figure 3. 

    The relationship between urinary albumin-creatinine (creat) ratio and other urinary markers. Scatter plots for all 3 study groups (antiretroviral treatment [ART]-naive [x], group exposed to tenofovir [TDF; filled circle], and group not exposed to tenofovir [non-TDF; open square]) show the relationship between urinary albumin-creat and (A) urinary retinol-binding protein (RBP)-creat ratios (rs = 0.53; P = 0.01); (B) urinary N-acetyl-β-d-glucosaminidase (NAG)-creat ratio (rs = 0.56; P = 0.01); and (C) urinary protein-creat ratio (rs = 0.20; P = 0.05).

Table 4. Agreement Between Urinary Markers in Detecting Abnormal Proteinuria
URBP/CUNAG/CUA/CUP/C
URBP/C—0.330.300.16
UNAG/C0.33—0.250.11
UA/C0.300.25—0.19
UP/C0.160.110.19—

Note: Values given as measures of agreement (κ [range, 0-1]).

Abbreviations: UA/C, urinary albumin-creatinine ratio; UNAG/C, urinary N-acetyl-β-d-glucosaminidase–creatinine ratio; UP/C, urinary protein-creatinine ratio; URBP/C, urinary retinol binding protein–creatinine ratio.

To evaluate the sensitivity of either UP/C or UA/C in detecting subclinical nephropathy, we compared proportions of patients in each group with increased values (greater than the normal upper limit) for UP/C or UA/C with the proportion with evidence of proximal tubular dysfunction (defined as increased URBP/C and/or UNAG/C; Fig 4). The proportion of patients in each group with proximal tubular dysfunction was considerably higher than proportions with either increased UA/C or UP/C (ART-naive, 10 of 19 [52.6%] vs 6 of 19 [31.6%] vs 4 of 16 [25.0%]; TDF, 38 of 47 [80.9%] vs 14 of 47 [29.8%] vs 24 of 46 [52.2%]; non-TDF, 27 of 33 [81.8%] vs 13 of 33 [39.4%] vs 9 of 30 [30.0%]). This implies that either UP/C or UA/C testing alone cannot reliably detect patients with ART-associated renal tubular dysfunction.

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  • Figure 4. 

    Sensitivity of either urinary albumin-creatinine ratio or protein-creatinine ratio in detecting renal tubular dysfunction. The proportion of patients with an increase (greater than the normal adult range) in either urinary albumin-creatinine (hatched bar) or protein-creatinine (gray bar) ratio was considerably lower than the proportion with abnormal tubular proteinuria (defined as increased urinary retinol-binding protein [RBP]-creatinine and/or N-acetyl-β-d-glucosaminidase [NAG]-creatinine ratio) (black bar) in all 3 study groups. Abbreviations: ARTN, antiretroviral therapy naive; non-TDN, group without exposure to tenofovir; TDN, group exposed to tenofovir.

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Discussion 

We have performed a cross-sectional study to investigate the nature and prevalence of subclinical renal tubular injury in patients with HIV without overt kidney disease. Our results show that the prevalence of proximal tubular dysfunction (increased URBP/C and/or UNAG/C) is high in both ART-naive patients and those on ART. Routine testing of either UP/C or UA/C alone is not sufficiently sensitive to detect these abnormalities.

Rates of tubular proteinuria were high in patients with HIV in a previous study19; however, no significant differences were found among different treatment groups. Subsequently, cross-sectional studies have shown an association between TDF exposure and increased urinary excretion of β2-microglobulin in both children20 and adults.21 Furthermore, a small longitudinal study reported that excretion of urinary β2-microglobulin increased significantly in patients after the start of TDF therapy.22 Although widely used as a marker of proximal tubular dysfunction, urinary β2-microglobulin has drawbacks as a screening tool because of its pH-dependence and enzymatic breakdown.23 RBP is believed to be a more reliable low-molecular-weight protein to measure.24

In our study, patients on ART (regardless of whether it included TDF) had significantly higher UNAG/C values compared with ART-naive patients. However, there were no significant differences in UA/C (a marker of glomerular disease) values. This suggests there is a background level of proximal tubular damage in patients on ART that is not specific for TDF. However, we have found that patients using TDF have higher URBP/C values than other patients with HIV (regardless of whether they are on ART), which could be explained by a more specific inhibitory effect of TDF on proximal tubular uptake and/or transport of low-molecular-weight proteins. This is consistent with the association of this drug with Fanconi syndrome in some case reports.

The level of agreement between the different urinary test results in our study in detecting abnormal proteinuria was low, and considerable numbers of patients with evidence of tubular dysfunction did not have an increased UA/C or UP/C. Furthermore, correlation between tubular markers and UP/C also was weak. Therefore, we propose that screening for increased urinary excretion of tubular proteins (such as URBP/C and UNAG/C) is a more appropriate strategy for monitoring patients using TDF than more conventional clinical tests for kidney disease (ie, UP/C or UA/C). This will need to be assessed in prospective longitudinal studies to identify patients at increased risk of TDF-associated renal toxicity. The finding that URBP/C values in our study were not normally distributed, and did not correlate with time on treatment, suggests that TDF toxicity in the kidney may be an “all or none” phenomenon (possibly because of underlying pharmacogenomic factors25). The significance of tubular proteinuria in predicting the development of chronic kidney disease is presently unknown, although it has been suggested that increased delivery of low-molecular-weight proteins to distal parts of the nephron might have pathophysiological consequences.26, 27

Renal phosphate wasting is one of the features of Fanconi syndrome. We did not observe significant differences in median serum phosphate levels among our study groups. However, there was a nonsignificant increase in the proportion of patients with hypophosphatemia in the TDF group, and this should be explored further in larger studies. Renal fractional excretion of phosphate was not measured in our study and we are unable to comment further on the mechanism of the effect of TDF on serum phosphate level.

We do not believe there have been major confounding factors in our study, because the different study groups were well matched and we excluded patients with diabetes or who were infected with hepatitis B or C virus. The incidence of hypertension and use of potentially nephrotoxic non-HIV therapy was low in all groups. Although the non-TDF group had received ART for a longer median time than the TDF group, we do not believe this weakens our findings. It is possible that even bigger differences in relative toxicity would have been observed between the 2 treatment groups had they been matched more closely for duration of therapy.

Our study was cross-sectional rather than longitudinal, and as such, we can only show associations between TDF exposure and renal tubular dysfunction and cannot establish causality. Furthermore, we cannot answer questions about progression of chronic kidney disease in patients using TDF, or recovery after discontinuation. Prospective randomized controlled trials are required to address these questions.

In summary, rates of subclinical proteinuria are high in patients with HIV. Those on ART, and in particular those using TDF, appear to be at increased risk. The long-term significance of these findings needs to be addressed in future studies, in particular, focusing on progression of chronic kidney disease and renal outcomes.

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Acknowledgements 

Support: This work was supported by grants awarded to Dr Hall by The Royal Free & University College London Medical School and Kidney Research UK.

Financial Disclosure: Dr Hall has previously received a lectureship fee from Gilead Sciences, which markets TDF.

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 Originally published online as doi:10.1053/j.ajkd.2009.07.012 on September 24, 2009.

PII: S0272-6386(09)01029-4

doi:10.1053/j.ajkd.2009.07.012

American Journal of Kidney Diseases
Volume 54, Issue 6 , Pages 1034-1042, December 2009

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