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doi: 10.1097/QAD.0b013e3283262a64
Clinical Science

Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir

Labarga, Pabloa; Barreiro, Pabloa; Martin-Carbonero, Luza; Rodriguez-Novoa, Soniab; Solera, Carmena; Medrano, Josea; Rivas, Pabloa; Albalater, Martac; Blanco, Franciscoa; Moreno, Victoriaa; Vispo, Eugeniaa; Soriano, Vincenta

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aInfectious Diseases Department, Spain

bPharmacology Unit, Hospital Carlos III, Madrid, Spain

cNephrology Department, Fundación Jimenez Diaz, Madrid, Spain.

Received 12 September, 2008

Revised 15 November, 2008

Accepted 11 December, 2008

Correspondence to Dr Vincent Soriano, Department of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, Madrid 28029, Spain. Tel: +34 91 4532500; fax: + 34 91 7336614; e-mail:

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Background: Tenofovir (TDF) is the most widely prescribed antiretroviral drug. Kidney abnormalities are the main concern using the drug. As glomerular function is infrequently affected in patients treated with TDF, herein, we report the results of an extensive examination of tubular function.

Methods: Cross-sectional study of plasma and 24 h urine markers of kidney tubulopathy (glucosuria, hyperaminoaciduria, hyperphosphaturia, hyperuricosuria and β2-microglobulinuria) could be allocated in three groups: patients under a TDF-containing HAART; patients on HAART never exposed to TDF; and antiretroviral-naive individuals. Significant tubular damage was defined when at least two of these parameters were repeatedly present, being at least one part of the Fanconi syndrome criteria (glucosuria, hyperaminoaciduria and hyperphosphaturia). Glomerular function was assessed using creatinine clearance.

Results: A total of 284 consecutive HIV patients were examined, 154 on TDF, 49 on other HAART regimens and 81 drug-naive. No significant differences in creatinine clearance were observed when comparing distinct groups. The proportion of patients with tubular damage in groups 1, 2 and 3 were 22, 6 and 12%, respectively. In a multivariate analysis [odds ratio (OR) {95% confidence interval (CI)} P], the only independent predictors of tubular dysfunction were TDF use (21.6, 4.1–113, <0.001) and older age (1.1 per year, 1.0–1.1, 0.01).

Conclusion: Exposure to TDF is associated with an increased risk over time of kidney tubular abnormalities in the absence of significant impaired glomerular function. Although long-term consequences of this tubulopathy are unknown, close monitoring of accelerated bone mineral loss and renal insufficiency are warranted. Periodic screening of tubular function parameters should be recommended to patients receiving TDF.

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Tenofovir disoproxil fumarate (TDF) (Viread; Gilead Sciences, San Francisco, California, USA) is the first nucleotide reverse transcriptase inhibitor licensed for the treatment of HIV infection [1]. The drug is also active against hepatitis B virus (HBV), and recently it has granted approval for this indication [2]. Given its convenience (one pill once daily), coformulation with other antiretrovirals (Truvada, Atripla), relatively good safety profile and robust antiviral activity, TDF is currently the most widely prescribed antiretroviral agent in Western countries [3]. Up to the end of year 2007, the cumulative patient TDF exposure in Europe and North America was estimated to be 455 392 person-years [4]. The overall good safety profile of TDF has been confirmed, with only sporadic cases of kidney disease, which generally have been reported in patients with predisposing renal illnesses or comorbidities such as diabetes [5–11].

Given that another two monophosphate nucleoside analogs, adefovir and cidofovir, licensed, respectively, for the treatment of hepatitis B and cytomegalovirus infections, are well known nephrotoxic agents in a dose-dependent manner [12–14], concerns have recently arisen regarding the long-term renal safety profile of TDF.

Tenofovir is uptaken at the kidney from the blood by the organic anion transporter (OAT), located on the surface of proximal tubular cells [15]. After two additional phosphorylations, the drug is extruded by the apical multidrug resistance protein (MRP) transporter into the tubular space, in which urine is formed. In agreement with this metabolism, most studies have emphasized that although patients treated with TDF may rarely experience any impairment in their glomerular function, as checked by measuring creatinine plasma concentrations or creatinine clearance [4,16], tubular damage may be more common and indeed case reports of kidney abnormalities on TDF have mainly been reported as Fanconi-like syndromes, a type of proximal tubular renal acidosis [5–11]. Given that HIV itself [17] and other antiretrovirals (e.g., indinavir) show nephrotoxic potential, there is a need to evaluate in detail renal tubular parameters in patients treated with TDF, trying to split out the influence of confounders.

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Material and methods

Study population

A prospective observational study was started in June 2007 at the HIV outclinic of Hospital Carlos III, a reference hospital for infectious diseases located in Madrid, Spain. All consecutive HIV-infected patients under regular follow-up were invited to participate in the study, as long as they could be allocated in any of the following three groups: patients under HAART currently receiving TDF for at least 3 months; patients under HAART never exposed to TDF; and HIV individuals never exposed to antiretroviral therapy.

Main demographics (age, sex, risk group, weight, chronic viral hepatitis and history of hypertension or diabetes mellitus) and HIV status (plasma HIV-RNA and CD4+ T-lymphocyte count) were recorded at the time of recruitment in the study. Total prior exposure to antiretroviral drugs was considered as the number of months of uninterrupted anti-HIV treatment up to inclusion, both in patients included in group 1 and 2; periods of drug interruption for any reason, if occurring, were discounted. This information was obtained by checking clinical charts and pharmacy records, as all patients recruited in the study had to obtain antiretroviral drugs on a monthly basis from the hospital pharmacy. Treatment was provided without any cost to patients.

The antiretroviral treatment modality, split out as based on protease inhibitors, nonnucleoside analogs or three nucleoside/nucleotide analogs, was recorded at the time of inclusion in the study. It should be noted that TDF was never given along with didanosine nor with stavudine in this study, given the increased risk of side-effects [18] and of selection of K65R [19], respectively using these combinations. A specific questionnaire was provided to all patients who accepted participation in the study asking about the use of drugs with nephrotoxic potential, particularly acetyl salicylic acid, nonsteroid anti-inflammatory drugs, valproic acid, cothrimoxazole, penthamidine, amphotericin B, gancyclovir or cidofovir. The study was approved by the hospital ethical committee, and all patients gave signed informed consent before inclusion in the study.

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Renal function tests

Within 1 month upon inclusion in the study, the main kidney glomerular and tubular parameters were determined in all patients in blood, drawn in fasting conditions and in 24 h urine. Venous blood biochemistry included creatinine, sodium, potassium, phosphorus, total calcium, uric acid, glucose, albumin, total proteins, pH and bicarbonate. In parallel, creatinine, phosphorus, calcium, uric acid, glucose, amino acids and β2-microglobulin were measured in 24 h urine. Creatinine clearance was calculated using the Dubois formula [(urine creatinine × urine volume)/(plasma creatinine × time)].

Proximal tubular renal dysfunction was determined on the basis of six criteria: glucosuria (urine glucose >300 mg daily) with normal glycaemia (plasma glucose <100 mg/dl); hyperaminoaciduria (any amino acid in urine, with the exception of hystidine, glycine and serine); fractional tubular resorption of phosphorus [1 − {(urine phosphorus × plasma creatinine)/(plasma phosphorus × urine creatinine)}] lower than 0.82; total excretion of phosphorus (urine phosphorus × urine volume) greater than 1200 mg daily; fractional excretion of uric acid [{(urine uric acid × plasma creatinine)/(urine creatinine × plasma uric acid)} × 100] greater than 15%; and β2-microglobulinuria greater than 1 mg daily [20]. Clinically, meaningful proximal tubular damage was defined when two or more of these parameters were present, being at least one of them any of the Fanconi syndrome-defining alterations (glucosuria in nondiabetic patients, hyperaminoaciduria or hyperphosphaturia) [21].

Arterial hypertension was considered in patients with history of hypertensive disease, regardless of being treated for this condition, or resting systolic blood pressure greater than 140 mmHg or diastolic blood pressure greater than 85 mmHg or both, at the time of recruitment [22]. Diabetic patients were identified as those with history of diabetes mellitus, receiving oral antidiabetic drugs or insulin or having fasting glycaemia greater than 110 mg/dl at recruitment [23].

Determination of urine β2-microglobulin was performed using inmunonephelometry (BN II DADE, Behring, Barcelona, Spain) and amino acids using high performance liquid chromatography (HPLC), following the PicoTag method (empower chromatrography with 2487 detecting ultraviolet radiations), as reported elsewhere [20].

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Statistical analyses

Continuous values are given as median [interquartile range (IQR)] and categorical data as percentages. The three groups of patients analyzed were first compared in a cross-sectional study using chi-squared for categorical data and parametric tests for continuous variables. Afterwards, a time-dependent study was performed taking into account time under TDF-containing HAART for group 1 versus time on antiretroviral treatment that did not include TDF for group 2. A Kaplan–Meier survival analysis was used to assess time until appearance of proximal tubular damage and comparisons between patients on HAART with and without TDF were made using log-rank test. Factors associated with tubular damage were examined by univariate and multivariate Cox proportional hazard regression models. A stepwise selection procedure was used to assess the relative role of prognostic factors. The level of significance was 0.05. All statistical analyses were performed using the SPSS v11 software package (SPSS Inc., Chicago, Illinois, USA).

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A total of 284 HIV patients were included in the study. At recruitment, 154 were under TDF (group 1), 49 on other HAART regimens and never exposed to TDF (group 2) and 81 were antiretroviral-naive (group 3).

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Characteristics of patients

Antiretroviral-naive patients were younger than patients under any HAART regimen, and patients receiving TDF had larger body weight than the rest (Table 1). Total duration on antiretroviral drugs was comparable in patients with and without TDF (59 versus 55 months, respectively). In group 1, median exposure to TDF was 36 months. The use of protease inhibitor tended to be more common in patients receiving TDF than other HAART regimens (57 versus 36%, respectively; P = 0.06). Plasma HIV-RNA levels and CD4 cell counts were comparable between these two groups. The rate of arterial hypertension or diabetes mellitus was similar in the three groups. Likewise, the history of exposure to nephrotoxic drugs was comparable between all groups. Finally, the prevalence of chronic hepatitis B and C was greater in patients treated with TDF than in the other two groups.

Table 1
Table 1
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Renal function

Kidney glomerular filtration, as measured by plasma creatinine levels or creatinine clearance or both, was overall within normal limits and comparable among study groups (Table 2). A total of 42 (14.8%) patients fulfilled the criteria of significant tubular damage at recruitment, using the definition previously described. Tubular dysfunction was more frequent in patients receiving TDF (22%) as compared with those never treated with TDF (6%) or never exposed to antiretrovirals (12%). The difference between drug-naive and patients on HAART not exposed to TDF did not reach statistical significance.

Table 2
Table 2
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Tubular impairment in patients under TDF as compared with those on HAART never exposed to TDF and drug-naive patients was mostly reflected by a lower fractional tubular resorption of phosphorus (0.82, 0.85 and 0.87 units, respectively) and a greater fractional excretion of uric acid (9, 7 and 7%, respectively). In agreement, plasma levels of uric acid differed between TDF patients and the other two groups (5.0, 5.6 and 5.6 mg/dl, respectively). Interestingly, β2-microglobinuria was greater in patients under TDF (250 μg/l) and drug-naive ones (235 μg/l) than in patients on HAART never exposed to TDF (210 μg/l). Finally, the rate of hypophosphoremia, nondiabetic glucosuria or aminoaciduria or all was greater in patients receiving TDF than in the rest, although without reaching statistical significance.

Three cases of complete Fanconi syndrome, as defined by abnormalities in all measured tubular parameters, were identified. All were seen in patients receiving TDF. In all cases, exposure to TDF had been for longer than 2 years. All showed a low fractional tubular resorption of phosphorus, ranging from 0.38 to 0.77, along with severe aminoaciduria and glucosuria. Interestingly, creatinine clearance was within normal values in all three patients, ranging from 79 to 118 ml/min. In one patient, urine abnormalities were accompanied by acidosis (pH, 7.30), low uric acid (1.8 mg/dl) and low phosphorus (1.5 mg/dl) in plasma.

Considering the duration of exposure to antiretrovirals, and comparing patients exposed and nonexposed to TDF, Fig. 1 shows the incidence of significant tubular dysfunction over time. Although the study began in June 2007 recruiting patients prospectively, the Kaplan–Meir curve shows the incidence of kidney tubular abnormalities in this population took into consideration prior to TDF exposure for each individual. After a median follow-up of 462 and 225 patients-year, those receiving TDF had significantly greater risk for tubular damage than patients never treated with TDF [odds ratio (OR) 18.9; P < 0.001]. According to this analysis, estimates for tubular dysfunction at 4 years were 25% for patients on TDF and null for the rest.

Fig. 1
Fig. 1
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Risk factors for kidney tubular damage

Of the 203 patients on HAART, complete data for the examination of risk factors associated with tubular damage could be obtained from 183 (90.1%) patients, of whom 33 belonged to the group with tubular dysfunction. Univariate analysis [OR, 95% confidence interval (CI)] showed that treatment with TDF (10.6, 3.0–37.4) or protease inhibitor (2.3, 1.1–4.8) was significantly associated with tubular damage (Table 3). Patients with diabetes (1.8, 0.9–3.6), lower CD4 cell counts (0.9, 0.9–1.1) and exposure to other nephrotoxic drugs (2.2, 0.9–5.1) tended to have abnormal tubular parameters. Multivariate analysis (OR, 95% CI, P) identified TDF use (21.6, 4.1–113, <0.001) and older age (1.1 per year, 1.0–1.1, 0.01) as the only independent predictors of tubular damage in this population.

Table 3
Table 3
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Although gastrointestinal disturbances have been the most frequent side-effects reported in clinical trials that have assessed the efficacy and safety of TDF [4,24–26], kidney events are the most worrisome [27], especially considering the experience with other monophosphate nucleoside analogs such as adefovir and cidofovir [12–14]. Acute renal failure and progressive renal insufficiency, however, have only been reported sporadically in patients treated with TDF and generally seen in patients with predisposing renal illnesses, comorbidities or use of potential nephrotoxic agents or all [5–11]. It should be noted, however, that a significant impairment in the renal function mainly reflects a substantial compromise in the glomerular filtrate. Primary tubular abnormalities, even severe, may be missed until they affect the glomerular function. Moreover, if tubular damage persists for long periods in the absence of significant renal insufficiency, clinical and laboratory manifestations other than those typically associated with kidney failure may develop. This is the case for premature osteoporosis due to bone mineral loss. Our study focused on tubular dysfunction in a relatively large number of HIV patients exposed to TDF for long periods and controls. With this design, it was permitted to collect relevant information on the unique tubular-associated toxicity of TDF.

Our study assessed in parallel glomerular and tubular parameters of kidney function in HIV individuals, adjusting for exposure to TDF and other antiretroviral agents and taking as controls HIV-untreated individuals. The last group is important as HIV has been shown to be directly involved in renal damage, particularly in blacks [17]. The assessment of tubular damage was exhaustive, measuring multiple variables in urine collected during the last 24 h. In this regard, we are confident that our estimates of tubular dysfunction are accurate. Although no signs of renal insufficiency were noticed in the study population, as reflected by creatinine plasma levels and creatinine clearance in 24 h urine, up to 22% of HIV patients treated with TDF showed two or more abnormal parameters used to assess tubular dysfunction. In contrast, this observation was found in only 6% of patients treated with other HAART regimens and in 12% of antiretroviral-naive patients.

The disconnection we found between the results of glomerular filtrate and markers of tubular dysfunction merits further discussion. Our results support an overall lack of impact of TDF use on creatinine clearance, even when measured by tools other than the most accurate we used in 24 h urine (e.g., the Cockcroft–Gault method), and are in agreement with data from others [28–30]. In contrast with the numerous longitudinal studies that have assessed the glomerular function in patients treated with TDF, very few have been conducted checking prospectively tubular dysfunction [31]. Indeed, most anecdotal reports of acute or chronic renal failure in patients treated with TDF have been preceded or accompanied by severe tubular damage, including Fanconi syndrome [32,33]. In some cases, TDF-associated tubular damage was suspected following development of suggestive clinical symptoms or laboratory signs such as metabolic acidosis with low serum bicarbonate levels, hypophosphataemia [32] or hypokalaemia [34]. The factor which so far was still unknown is the true prevalence of TDF-associated tubulopathy in the absence of any recognizable compromise in the glomerular filtrate. It is noteworthy that our 22% rate being 6% in patients taking other HAART regimens.

What may be the clinical relevance of chronic tubulopathy in patients treated with TDF in the absence of a significant impairment in the glomerular function? At first glance, it is worth mentioning that a subset of patients may progress to renal insufficiency as time passes by, especially because older age reduces the threshold for renal insufficiency. However, the most important caveat regards the long-term consequences of chronic loss of phosphorus in the urine. Premature osteoporosis due to persistent hypophosphataemia may be a worrisome complication.

Given the cross-sectional nature of our study, we could not assess adequately the time-frames for the development of TDF-associated tubulopathy. From the literature, it seems that some individuals are particularly susceptible, and genetic predisposition may account for it [35–37]. In our series, the only patient presenting with a complete Fanconi syndrome with consequences recognizable in the blood had been exposed to TDF for 37 months. In other similar cases reported in the literature [5–11,32,33], the lapsed time ranged between 6 and 18 months.

Comorbidities such as diabetes, concomitant administration of nephrotoxic agents and use of protease inhibitors have all been associated with an increased risk of TDF-associated kidney disease. These conditions are relatively common in HIV patients. However, in our study, the multivariate analysis suggested that their role as cause of tubulopathy was only marginal. A review from the Food and Drug Administration noticed that some cases of Fanconi syndrome in patients treated with TDF occurred when using concomitantly either didanosine or protease inhibitors or both, which could had enhanced the nephrotoxicity of TDF [38]. In our series, no patient was treated with didanosine because prior concerns about CD4+ T lymphopenia [18]. Although protease inhibitors were used by 57% of our patients treated with TDF and their potential for increasing TDF-tubular damage has already been claimed by others [39], we could not find a significant association between their use and tubular damage in the multivariate analysis. Therefore, their role must be low, if any.

An interesting finding in our study was the recognition of an increased rate of tubular dysfunction parameters in antiretroviral-naive patients compared with those on HAART who did not receive TDF. As β2–microglobulin concentrations in urine are a sensitive marker of tubular damage, often preceding other signs of tubular injury [40,41], we concentrated on this marker. Up to 9.4% of drug-naive patients in our series showed a high urinary excretion of β2–microglobulin. This finding indirectly supports that HIV itself might cause tubular damage to some extent, as has been suggested by others [42–44]. The fact that our patients on HAART including TDF, conversely, showed the greatest levels of β2–microglobulin in urine reinforces the unique potential for tubular toxicity of TDF. Indeed, some authors have defended monitoring urine β2–microglobulin in patients on TDF in an attempt to identify the subset of individuals at increased risk for renal injury [45].

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Our results confirm that exposure to TDF is associated with signs of proximal tubular kidney damage, often in the absence of any significant impairment of the glomerular function, in a substantial proportion of HIV patients. Although the clinical long-term consequences of this observation are currently unknown, it seems worth while to periodically monitor for signs of tubular damage in HIV patients on TDF and to consider a switch in therapy if signs of progressive deterioration are manifest. Our findings in HIV patients should be viewed as relevant also for chronic hepatitis B, as most of these patients will need long periods (often years) of treatment [2]. A periodic monitoring of tubular parameters would be warranted in this population as well.

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This work was funded in part by grants from Fundación Investigación y Educación en SIDA (IES), the European NEAT consortium, Agencia Lain Entralgo and Red de Investigación en SIDA (RIS, ISCIII-RETIC RD06). We would like to thank Professor Juan Gonzalez-Lahoz for comments and continuous support.

P.L., M.A. and V.S. designed the study. P.L., C.S., P.R., L.M.-C., P.B., F.B., V.M., E.V., S. R.-N. and V.S. enrolled patients in the study and collected data. P.L., J.M., P.B. and L.M.-C. did the statistical analyses and interpretations. P.L. and V.S. wrote the first draft of the manuscript.

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Back to Top | Article Outline

bone; Fanconi syndrome; HIV; kidney; tenofovir

© 2009 Lippincott Williams & Wilkins, Inc.


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