The widespread use of effective combination antiretroviral therapy (cART) has decreased AIDS-associated mortality, increasing life expectancy . However, prolonged cART could favor an increased incidence of long-term complications, such as renal involvement .
Between the different antiretroviral drugs, tenofovir, disoproxil, fumarate (TDF) is widely recommended as a first-line therapy in HIV treatment . Clinical trials suggest that TDF has a low overall toxicity profile, with a significant but modest effect on decreasing estimated glomerular filtration rate (eGFR) . However, several studies showed an increased prevalence of renal tubular dysfunction in TDF-treated patients in comparison with patients receiving other cART regimens [5,6].
In-vitro and animal studies support the notion that mitochondria are the major targets of TDF toxicity in the kidney, and drug accumulation of this drug in the tubule cells seems to be the pathogenic mechanism for tubular dysfunction . However, to date, there are few data about the clinical significance and correlation of different tubular abnormalities with kidney function decline. Even, there are no clear criteria of which is considered as ‘tubular dysfunction’, the influence on tubular parameters of other factors such as hepatitis C virus (HCV) coinfection, diabetes mellitus or hypertension arterial (HTA), or the number of tubular abnormalities of clinical significance .
Thus, we evaluate the prevalence and significance, in terms of renal function decline, of tubular abnormalities in HIV-infected patients with measurements of different serum and urinary parameters.
We present a cross-sectional evaluation of patients included in an ongoing cohort study of renal and bone involvement among HIV-infected patients. In this cohort, baseline and sequential determinations of serum creatinine, phosphate, albumin, glucose and lipids are performed in every visit since therapy initiation. From January 2014 through July 2015, a cross-sectional evaluation of urinary parameters including proteinuria, albuminuria, phosphaturia, uricosuria, and glycosuria was obtained in consecutive patients to analyze the prevalence and significance of tubular abnormalities.
We included in this study HIV-infected patients receiving a cART regimen containing TDF without changes in the accompanying drugs, and who had two available consecutive urine measurements in a period of at least 3 months. We excluded patients younger than 18 years, and those receiving other nephrotoxic drugs (including nonsteroideal anti-inflammatory drugs or anticancer chemotherapy). But, to control the influence of other variables and of the former use of TDF, two different subgroups of patients, following TDF discontinuation (previous TDF), or who never received TDF (never TDF) were mandatorily included.
The study was approved by our institutional review board (EC 039/14), and written informed consent was obtained from every participant. The study was registered at ClinicalTrials.gov (NCT 02116751).
Demographic data (age, sex, body mass index), HIV-related data (risk practice, time of HIV infection, nadir and baseline CD4+ cell count, latest precART HIV-1 viral load, previous cART), and hepatitis C virus (HCV) coinfection status were collected for each patient at the time of inclusion. A diagnosis of hypertension or diabetes mellitus was recorded in all the cases. As mentioned, routine physical examination and laboratory tests, including serum creatinine, phosphate, calcium, total protein, total cholesterol, triglycerides, and CD4+ cell counts and HIV-1 RNA levels [Versant HIV-1 RNA 1.0 (kPCR), Siemens Diagnostics, Munich, Germany; quantification limit 37 copies/ml] were available every 3–4 months since cART initiation (mean, nine serum sample determinations, range 3–21, similar between groups). As part of the study, serum glucose, creatinine, phosphate, and urinary protein, albumin, creatinine, uricosuria, phosphaturia, and glycosuria in the first urine of the morning were performed at inclusion and confirmed in a period of at least 3 months, using these confirmatory values for analysis. eGFR was calculated using the chronic kidney disease (CKD)-epi equation .
Urine total protein was measured by using benzethonium chloride method and urine albumin by immunoturbimetric assay. Both were expressed as a ratio to creatinine in mg/gr (urinary albumin/creatinine ratio, uACR; urinary protein/creatinine ratio, uPCR). Urine creatinine concentration was determined by an enzymatic method. The albumin to protein ratio (APR) was determined by dividing ACR by uPCR. Phosphaturia was determined as fractional excretion (FE) of phosphate: [(urine phosphate × serum creatinine)/(urine creatinine × plasma phosphate)]×100. Uricosuria was measured as fractional excretion of uric acid: [(urine uric acid × serum creatinine)/(urine creatinine × plasma uric acid)] × 100.
Hypertension or diabetes mellitus were defined as a systolic/diastolic blood pressure at least 140/90 mmHg or the use of antihypertensive agents, or as a previous diagnosis or use of oral antidiabetic agents or insulin, respectively.
Proteinuria was defined as an uPCR greater than 100 mg/dl (11.3 mg/mmol), macroalbuminuria as uACR greater than 300 mg/g (approximately >30 mg/mmol), and microalbuminuria as uACR 30–300 mg/g (3–30 mg/mmol), respectively. Hyperphosphaturia of tubular origin, also referred as phosphate diabetes, was defined as a fractional excretion of phosphate greater than 20%. Confirmed hypophosphatemia was defined as a serum phosphate at least 2.5 mg/dl in two successive determinations, excluding chronic diarrhea or alcoholism. Hyperuricosuria was defined as a fractional excretion of uric acid at least 10% . Glycosuria was defined as a value above 100 mg/dl (5.56 mmol/l), the threshold of our laboratory in nonpregnant patients, in presence of normal glycemia (plasma glucose <125 mg/dl). Proximal renal tubular dysfunction (PRTD) was defined as the presence of at least two tubular abnormalities: phosphaturia, nondiabetic glycosuria, hyperuricosuria, hypophosphatemia, or/and proteinuria.
Renal function change was defined as a sustained modification of eGFR in ml/min per 1.73 m2 with respect to the value before current cART initiation. CKD was established if eGFR values were lower than 60 ml/min per/1.73 m2 in two determinations (CKD stage 3 or higher) according to the guidelines for CKD of the National Kidney Foundation .
The primary end points were the prevalence of tubular abnormalities and the correlation of tubular alterations with eGFR changes. As secondary end points, the causes of tubular abnormalities were evaluated. As mentioned, exposure to cART was categorized as current TDF, cART not containing TDF after discontinuation (previous TDF), and naive/cART never including TDF. Time at risk began upon TDF (or current cART) initiation and continued until inclusion. Cumulative exposure to cART was considered as the number of months of treatment since any antiretroviral regimen initiation up to inclusion.
Characteristics of patients according to use of TDF and the number of tubular abnormalities were compared for statistical significance using the Mann–Whitney U-test for continuous variables and the χ2-square test for categorical variables. Analysis of paired observations was performed using the Wilcoxon rank t-test. Correlations between the different tubular parameters obtained in the confirmatory urine sample, were assessed using Pearson's correlation coefficient. A multivariable analysis using logistic regression evaluated factors associated with the presence of PRTD, adjusted for potential confounders of kidney disease, by using the backward stepwise method. A linear regression model was created utilizing changes in eGFR since current cART initiation as the dependent variable, considered as numerical (ml/min per 1.73 m2). All P-values are two-sided and a value of P < 0.05 was considered statistically significant.
To date, a total of 266 patients with successive serum determinations had been included into the cohort, but 18 patients changed some drug of the cART regimen and were not included for evaluation of urine parameters. None of these 18 changes were due to renal toxicity. Thus, finally, 248 patients met the predefined criteria: 200 receiving TDF – current TDF, 26 receiving a cART regimen following TDF discontinuation – previous TDF, and 22 patients not previously treated with TDF – never TDF. Baseline characteristics of the patients according to the use of TDF are shown in Table 1. Of note, mean age was 43.6 years. Among patients never treated with TDF, 11 of the 22 patients were naive (50%). There were differences between the groups for the proportion of former IDUs, HCV coinfection, or the prevalence of HTA. Indeed, patients who had interrupted TDF represent an older, largely pretreated population, with higher prevalence of HCV coinfection and HTA than current-TDF patients (cumulative time on ART, 198 versus 143 months; P < 0.01). On the other hand, sex, BMI, nadir and baseline CD4+ cell count were similar between groups.
The median length of time on TDF was 64.6 months [interquartile range (IQR) 42.7–84.7; cumulative time 1080.4 patients-year on TDF]. Previous-TDF-treated patients had received this NRTI for a median time of 46.5 months (IQR, 22.6–62.3), and were receiving a TDF-free regimen for 41.2 months (IQR, 25.6–74.5), whereas patients never treated with TDF were receiving cART in 11 cases for a median time of 73.2 months (IQR, 70.3–89), or had a follow-up of 58.7 months (IQR, 38.3–65.6) in case of naïve patients.
Of the 200 patients on TDF treatment, 58 (29%) were on first line cART regimen, and the remaining 142 had received a mean of two previous cART regimens. Importantly, 127 were receiving a TDF and a nonnucleoside (mainly efavirenz as single tablet regimen, 74 cases). At current cART initiation, current-TDF patients had a mean eGFR of 97.6 ml/min per 1.73 m2 (range, 51–145), only four patients had a value below 60 ml/min per 1.73 m2 (2%), and, as expected, there were differences between first-line and pretreated patients (101.4 versus 95.8 ml/min per 1.73 m2; P = 0.03). The lowest eGFR baseline level was observed in previous-TDF-treated patients (mean eGFR 83.1 ml/min per 1.73 m2).
A significant decrease in eGFR was observed from cART initiation to urinary evaluation, that was inversely correlated with time on TDF (r = –0.19; P < 0.01; Fig. 1a), and it was greater in patients receiving TDF and a protease inhibitor than in those taking TDF and a nonnucleoside reverse-transcriptase inhibitor (–10.1 versus –5.1 ml/min per 1.73 m2; P < 0.01; Fig. 1b). Overall, 58% of the 200 patients taking TDF presented a confirmed decrease in eGFR whereas both groups not receiving TDF improved eGFR during a similar time of follow-up (+5.7 and +2.1 ml/min per 1.73 m2 for previous and never TDF; 61 and 70% improved, respectively).
At inclusion, 273 tubular abnormalities were found in the 248 patients. At least one alteration was found in 72% of patients, mainly in patients with current (75%) or previous (85%) use of TDF. On the other hand, most patients (73%) never treated with TDF had no urinary alteration at all. Moreover, as shown in Table 2, two or more tubular abnormalities defining PRTD were found in 63 (32%), 6 (23%), and 0 patients with current-, previous-, or never-TDF use.
Amongst the different tubular abnormalities, proteinuria at least 100 mg/gr was found in 40% of cases (13% with uPCR ≥ 150 mg/g), and there were no differences in patients with current or previous use of TDF (Table 2), in comparison with three cases (14%) of never-TDF users (P = 0.02). Of note, no patient had macroalbuminuria and mean APR was 0.12. In absence of hyperglycemia, glycosuria was present in 10%, 2 (8%), and 0 patients respectively. Phosphate wasting, as defined, was found in 46, 42, and 14% (P < 0.01 between both TDF groups and never TDF). Of note, patients in the never-TDF group having proteinuria or phosphaturia had the longest time of HIV infection and previous ART.
There was a significant correlation (P < 0.01) between the different tubular parameters, especially between proteinuria and glycosuria (r = 0.62), phosphaturia (r = 0.24), and uricosuria (r = 0.43). Glycosuria was correlated with a higher fractional excretion of phosphate in urine (r = 0.25). Phosphatemia was inversely correlated with phosphaturia (r = –0.45). Of note, these correlations were closest when only current-TDF users were evaluated. Thus, proteinuria correlated significantly with glycosuria (r = 0.77), phosphaturia (r = 0.31), and uricosuria (r = 0.48), and also glycosuria and phosphaturia (r = 0.33) were correlated.
Characteristics of patients without, and with 1, and 2 or more tubular abnormalities are given in Table 3. Older age, use of TDF, diabetes mellitus, HTA, HCV coinfection, time of HIV infection, cumulative time of cART, and lower eGFR at baseline were associated with PRTD. Of note, time on cART and time of HIV infection were progressively longer in case of more tubular abnormalities, but time on TDF did not reach statistical significance. In a multivariate logistic regression analysis, cumulative time on cART [odds ratio (OR) 1.011; 95% confidence interval (CI) 1.07–1.019 per month; P = 0.01], initial eGFR (OR 0.97; 95%CI 0.94–0.99 per ml/min per 1.73 m2 higher; P = 0.04), and use of TDF (OR 13.2; 95%CI 1.4–22.7; P = 0.01) were associated with PRTD, after adjusting by age, risk practice for HIV infection, time of HIV infection, HCV coinfection, and HTA/diabetes mellitus diagnosis.
In a sub-analysis of patients receiving TDF, excluding those with HTA, diabetes mellitus, or HCV coinfection, at least one tubular abnormality was found in 33 of 49 patients receiving first-line therapy (67%) and PRTD in nine (18%), after a longer, albeit not significant, time on TDF therapy (53.2 versus 41 months; P = 0.13). Indeed, the prevalence of PRTD was three out of 22 patients after 3 years of exposure (14%), and seven out of 41 after 5 years on TDF (17%). Also, in 63 pretreated patients, 46 (73%) of patients had tubular abnormalities and 17 (27%) PRTD, and again, there was a not significant trend to increase with longer time on TDF (one out of six at 3 years, 17%; six out of 24 at 5 years, 25%). On the other hand, patients receiving TDF and having HCV coinfection, HTA or diabetes mellitus had the highest prevalence of tubular abnormalities (84%) and PRTD (31 out of 74, 46%). Independently from line of therapy, prevalence of hypophosphatemia, phosphaturia, nondiabetic glycosuria, and hyperuricosuria were similar (15, 48, 7, 21%, respectively) but proteinuria was lower (31%) and microalbuminuria was very rare (3%) in absence of HTA, diabetes mellitus or HCV coinfection.
Correlation between tubular abnormalities and renal function decline
Overall, a greater eGFR decline from cART initiation was observed in patients showing a higher number of tubular abnormalities (Fig. 2). Mean eGFR decline prior to inclusion was greater according to the number of tubular abnormalities (+0.46, –0.49, –1.7, and –6.7 ml/min per 1.73 m2; P = 0.04 between 0 and 3), and even higher in case of current TDF use (+0.33, –2.7, –2.1, –5.1, and –8.2; P = 0.03 between 0 and 2). This decrease led to a higher, but relatively small, number of CKD diagnosis (one, seven and six patients, for zero, one and two or more tubular alterations, respectively).
There was a significant, although moderate, correlation between the different tubular abnormalities and eGFR change. Thus, FE of uric acid (r = –0.27, P < 0.01), phosphaturia (r = –0.46; P < 0.01), uPCR (r = –0.19; P < 0.01), and glycosuria (r = –0.2; P = 0.02) were associated with a lower value of eGFR. In the linear regression analysis, the number of tubular abnormalities was independently associated with changes in eGFR since cART initiation (β coefficient –0.15, P = 0.02), together with age (–0.18, P = 0.01), eGFR at cART initiation (β coefficient, 0.49, P = 0.01), diabetes mellitus (–0.19, P = 0.02), and time on TDF (–0.23, P = 0.01).
Our study, in a well controlled population of HIV-infected patients receiving TDF in the clinical setting, shows that around two-thirds of patients had at least one of the tubular abnormalities known to be associated with Fanconi's syndrome, and 32% of patients presented two or more tubular alterations after a median time of 5 years. Moreover, these data contrast to those of patients never treated with TDF.
As it has been demonstrated, the proximal tubule is intrinsically vulnerable to mitochondrial alteration secondary to TDF, even after 5 weeks, showing an increased number and irregular shape of mitochondria, parallel to a decrease in mtDNA [7,12,13]. However, the rate and presentation of tubular involvement varies, in probable relation with the risk factors included, the use of beta-2-microglobulin (B2M) or retinol-binding protein (RBP), which could be more sensitive, or to the time on TDF before to be evaluated [5,6,8,14,15]. Moreover, drug interactions and underlying genetic polymorphisms might help explain why TDF accumulates more in tubule cells in some patients .
In any case, mounting evidence supports that tubular abnormalities should be included between the toxicity of TDF in the middle term. Dauchy et al. described PRTD in 6.5% of nearly 300 patients, after median exposure to TDF of 16.3 months, whereas Gatanaga described a prevalence of tubular damage, defined by increased urinary B2M level, of 43% of patients on TDF after a mean of 13 months. Ezinga et al. described tubular abnormalities in 63% of 161 patients, with 11% fulfilling the definition of PRTD after a mean of 46 months on TDF. Also, Labarga et al. described a prevalence of tubular dysfunction of 22% in 153 patients receiving TDF for a median time of 36 months [5,14,17,18]. We found an overall prevalence of PRTD of 32%, but it ranged from 14% for first-line TDF-treated patients without other classical risk factors at 3 years of TDF exposure, to 46% of patients with concomitant HCV coinfection, HTA and/or diabetes mellitus.
In addition, this work clarifies the type and causes of tubular abnormalities. Previous studies suggest that HIV infection might directly affect tubular cells . However, we found a close relationship between use of TDF and rate of tubular abnormalities, and they were rare in naive patients. Indeed, age and use of TDF have been consistently associated with tubular damage [5,6], and also, PRTD has been described in non-HIV-infected patients receiving long-term adefovir, also attributed to mitochondrial toxicity . We included the importance of a lower baseline eGFR that could be a marker of older age, HCV coinfection, HTA, or diabetes mellitus, but that also has been associated with higher exposure to TDF in pharmacokinetic analysis . In any case, we demonstrate by the first time a significant correlation between the different tubular parameters. Taken together, these data suggest that tubular dysfunction is a complex interplay of baseline renal function and use of TDF, influenced in some patients by age, HIV itself, HCV coinfection, HTA, diabetes mellitus, and probably by genetic susceptibility.
Previously, a meta-analysis concluded that TDF-treated patients experienced a significant but small loss of kidney function during the course of treatment , but randomized studies did not include a full evaluation of tubular parameters with the exception of proteinuria . Moreover, clinical trials select patients without preexisting kidney function alteration and the follow-up is relatively short. Of clinical importance, we demonstrate a relationship between the number of tubular abnormalities and kidney function decline since TDF initiation. We evaluated eGFR changes prior to the cross-sectional evaluation of tubular dysfunction, and therefore, the association between tubular abnormalities and eGFR decline, although significant, could indicate different pathogenic mechanisms related with TDF (i.e. tubular injury and simultaneous inhibition of tubular creatinine excretion) . But, supporting our data, in a large study, Scherzer et al. found an independent association between TDF and increased risk of proteinuria, rapid decline in kidney function, and CKD , and Shlipak et al. recently described a strong and independent association of the high tertiles of biomarkers of tubular damage with a faster rate of annual kidney function decline among HIV-infected women . As an indirect confirmation, a significant lower incidence of tubular abnormalities and eGFR decline has been observed in preliminary studies by using tenofovir alafenamide (TAF), a novel prodrug of TDF reaching lower concentrations in tubular cells .
Indeed, increased proteinuria is a known cause of kidney function decline , and hypothetically, the low-grade proteinuria (tubular) observed with TDF could explain the slow decrease of eGFR in absence of other classical factors. In our study, risk factors for eGFR decline were age, time on TDF, eGFR at initiation, diabetes mellitus and presence of tubular abnormalities. Thus, these data suggest that time on TDF and the progressive tubular involvement led to eGFR fall, a fact modulates by age and other known factors of renal involvement [15,29]. We cannot establish when TDF could worsen latent tubular injury in some patients with advanced age, diabetes mellitus, or with lower baseline eGFR, due to the lack of data about urinary parameters at cART initiation in the TDF-treated group. However, our results with the inclusion of two control groups suggest a direct role for tubular injury and eGFR decline secondary to TDF.
Proteinuria was found in almost half of patients receiving TDF, defined as an uPCR at least 100 mg/g, a lower limit than that usually considered as pathologic (150–200 mg/g), but similar to the reference range for adults (115 mg/g), to that observed in naïve patients, and to that described when dipstick is used as screening (2+, ≥100 mg/g) . Indeed, tubular proteinuria is mainly composed of low-molecular-weight proteins, and a large amount of proteins in urine is not expected in case of tubular dysfunction [8,31]. Of clinical importance, albuminuria was rare and it was not useful as marker of tubular involvement . A previous study found an APR less than 0.4 as highly suggestive of tubular toxicity , but we found that this ratio was usually lower than 0.2.
The most frequent tubular abnormality was a lower reabsorption of phosphate. Previous in-vitro studies have suggested that phosphate transport in the proximal tubule is particularly sensitive to mitochondrial toxicity , and increased urinary phosphate excretion has been previously associated with TDF use [6,14,35,36]. We observed a clear association between phosphaturia and eGFR decline, and a significant correlation with phosphatemia.
Our study offers indirect data about the reversibility of tubular dysfunction after TDF withdrawal. In general, partial improvement and persistent damage has been reported [37,38]. In our patients who discontinued TDF, after 41 months, nearly half of patients continued to have proteinuria and phosphaturia, but there was a significant increase in eGFR value and the rate of PRTD was lower, despite that these patients were older, largely pretreated, and had a greater prevalence of HTA, diabetes mellitus, or HCV coinfection, suggesting improvement, at least in part. Unfortunately, we are unable to estimate the rate of improvement due to the lack of urinary parameters at the time of TDF discontinuation.
Our study has several limitations. This study was conducted among patients in routine care and cART regimen was not randomly assigned. However, patients were excluded if they were receiving nephrotoxic drugs, which could even minimize the rate of toxicity attributed to TDF. Moreover, the role of classical risk factors for renal toxicity and pretreatment was also evaluated and two control groups were included. In addition, changes in any drug of the cART regimen were not permitted, allowing us to directly examine associations between drug-exposure and dysfunction. Finally, we did not include tubular proteins such as B2M or RBP, which have shown to be more sensitive for identifying tubular dysfunction . However, further studies are required to determine its sensitivity and specificity. On the other hand, proteinuria (probably considering a lower threshold), increased fractional excretion of phosphate and glycosuria are easy to screen for.
In conclusion, our study suggests that the use of, and time on TDF, modulated by other factors such as age, baseline renal function, or classical risk factors, leads to the progressive wasting in the urine of substances that are normally reabsorbed by the proximal tubule, such as low-molecular-weight proteins, phosphate or glucose. Although CKD was rare during follow-up, the number of tubular abnormalities was associated with greater kidney function decline. Thus, the risks of nephrotoxicity associated with TDF have to be balanced with the benefits of the drug as an effective treatment for HIV infection.
This study did not receive specific funding.
We would like to thank Ana Abad for their important contribution in database management.
Author contribution: J.L.C., F.L., and J.M.R. conceived and designed the study, and were responsible for patient enrollment, follow-up, data analysis and drafted and finalized the article, C.S., J.S., and P.G. conceived and performed analytical evaluations, and S.B., M.T. were responsible for patient enrollment, clinically followed-up patients, and helped to write the work. All coauthors revised the manuscript and read and approved the final version.
Conflicts of interest
Conflict of interest and source of funding: J.L.C. has received grants for investigation from Janssen and Gilead. For the remaining authors none was declared. All research was conducted within the guidelines of ethical principles, and local legislation.
1. Mocroft A, Brettle R, Kirk O, Blaxhult A, Parkin JM, Antunes F, et al. Changes in the cause of death among HIV positive subjects across Europe: results from the EuroSIDA study
2. Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, et al. Premature age-related comorbidities among HIV-infected persons compared with the general population
. Clin Infect Dis
3. Expert Panel of GESIDA and the National Aids Plan, Berenguer J, Polo R, Lozano F, Lopez Aldeguer J, et al.. Executive summary of the GeSIDA/National AIDS Plan Consensus Document on antiretroviral therapy in adults infected by the human immunodeficiency virus (updated January 2014)
. Enferm Infect Microbiol Clin
4. Izzedine H, Hulot JS, Vittecoq D, Gallant JE, Staszewski S, Launay-Vacher V, et al. Long-term renal safety of tenofovir disoproxil fumarate in antiretroviral-naive HIV-1-infected patients. Data from a double-blind randomized active-controlled multicentre study
. Nephrol Dial Transplant
5. Dauchy FA, Lawson-Ayayi S, de La Faille R, Bonnet F, Rigothier C, Mehsen N, et al. Increased risk of abnormal proximal renal tubular function with HIV infection and antiretroviral therapy
. Kidney Int
6. Labarga P, Barreiro P, Martin-Carbonero L, Rodriguez-Novoa S, Solera C, Medrano J, et al. Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir
7. Lebrecht D, Venhoff AC, Kirschner J, Wiech T, Venhoff N, Walker UA. Mitochondrial tubulopathy in tenofovir disoproxil fumarate-treated rats
. J Acquir Immune Defic Syndr
8. Del Palacio M, Romero S, Casado JL. Proximal tubular renal dysfunction or damage in HIV-infected patients
. AIDS Rev
9. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate
. Ann Intern Med
10. Simkin PA, Hoover PL, Paxson CS, Wilson WF. Uric acid excretion: quantitative assessment from spot, midmorning serum and urine samples
. Ann Intern Med
11. Kidney Disease: Improving Global Outcomes CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)
. Kidney Int Suppl
12. Kohler JJ, Hosseini SH, Hoying-Brandt A, Green E, Johnson DM, Russ R, et al. Tenofovir renal toxicity targets mitochondria of renal proximal tubules
. Lab Invest
13. Ramamoorthy H, Abraham P, Isaac B. Mitochondrial dysfunction and electron transport chain complex defect in a rat model of tenofovir disoproxil fumarate nephrotoxicity
. J Biochem Mol Toxicol
14. Calmy A, Fux CA, Norris R, Vallier N, Delhumeau C, Samaras K, et al. Low bone mineral density, renal dysfunction, and fracture risk in HIV infection: a cross-sectional study
. J Infect Dis
15. Kinai E, Hanabusa H. Progressive renal tubular dysfunction associated with long-term use of tenofovir DF
. AIDS Res Hum Retroviruses
16. Rodriguez-Novoa S, Labarga P, Soriano V, Egan D, Albalater M, Morello J, et al. Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir: a pharmacogenetic study
. Clin Infect Dis
17. Ezinga M, Wetzels JF, Bosch ME, van der Ven AJ, Burger DM. Long-term treatment with tenofovir: prevalence of kidney tubular dysfunction and its association with tenofovir plasma concentration
. Antivir Ther
18. Gatanaga H, Tachikawa N, Kikuchi Y, Teruya K, Genka I, Honda M, et al. Urinary beta2-microglobulin as a possible sensitive marker for renal injury caused by tenofovir disoproxil fumarate
. AIDS Res Hum Retroviruses
19. Conaldi PG, Biancone L, Bottelli A, Wade-Evans A, Racusen LC, Boccellino M, et al. HIV-1 kills renal tubular epithelial cells in vitro by triggering an apoptotic pathway involving caspase activation and Fas upregulation
. J Clin Invest
20. Gara N, Zhao X, Collins MT, Chong WH, Kleiner DE, Jake Liang T, et al. Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B
. Aliment Pharmacol Ther
21. Baxi SM, Greenblatt RM, Bacchetti P, Scherzer R, Minkoff H, Huang Y, et al. Common clinical conditions - age, low BMI, ritonavir use, mild renal impairment - affect tenofovir pharmacokinetics in a large cohort of HIV-infected women
22. Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients
. Clin Infect Dis
23. Gallant JE, Winston JA, DeJesus E, Pozniak AL, Chen SS, Cheng AK, et al. The 3-year renal safety of a tenofovir disoproxil fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients
24. Vrouenraets SM, Fux CA, Wit FW, Garcia EF, Furrer H, Brinkman K, et al. Persistent decline in estimated but not measured glomerular filtration rate on tenofovir may reflect tubular rather than glomerular toxicity
25. Scherzer R, Estrella M, Li Y, Choi AI, Deeks SG, Grunfeld C, et al. Association of tenofovir exposure with kidney disease risk in HIV infection
26. Shlipak MG, Scherzer R, Abraham A, Tien PC, Grunfeld C, Peralta CA, et al. Urinary markers of kidney injury and kidney function decline in HIV-infected women
. J Acquir Immune Defic Syndr
27. Mills A, Crofoot G Jr, McDonald C, Shalit P, Flamm JA, Gathe J Jr, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate in the first protease inhibitor-based single-tablet regimen for initial HIV-1 therapy: a randomized phase 2 study
. J Acquir Immune Defic Syndr
28. Abbate M, Zoja C, Remuzzi G. How does proteinuria cause progressive renal damage?
. J Am Soc Nephrol
29. Ando M, Yanagisawa N, Ajisawa A, Tsuchiya K, Nitta K. Kidney tubular damage in the absence of glomerular defects in HIV-infected patients on highly active antiretroviral therapy
. Nephrol Dial Transplant
30. Rhee MS, Schmid CH, Stevens LA, Forrester JE. Risk factors for proteinuria in HIV-infected and -uninfected Hispanic drug users
. Am J Kidney Dis
31. Gravemann S, Brinkkoetter PT, Vehreschild JJ, Franke B, Ehren K, Bunemann E, et al. Low-grade proteinuria is highly prevalent in HIV-positive patients on antiretroviral treatment
32. Campbell LJ, Dew T, Salota R, Cheserem E, Hamzah L, Ibrahim F, et al. Total protein, albumin and low-molecular-weight protein excretion in HIV-positive patients
. BMC Nephrol
33. Samarawickrama A, Cai M, Smith ER, Nambiar K, Sabin C, Fisher M, et al. Simultaneous measurement of urinary albumin and total protein may facilitate decision-making in HIV-infected patients with proteinuria
. HIV Med
34. Gullans SR, Brazy PC, Soltoff SP, Dennis VW, Mandel LJ. Metabolic inhibitors: effects on metabolism and transport in the proximal tubule
. Am J Physiol
35. Harris M. Nephrotoxicity associated with antiretroviral therapy in HIV-infected patients
. Expert Opin Drug Saf
36. Woodward CL, Hall AM, Williams IG, Madge S, Copas A, Nair D, et al. Tenofovir-associated renal and bone toxicity
. HIV Med
37. Bonjoch A, Echeverria P, Perez-Alvarez N, Puig J, Estany C, Clotet B, et al. High rate of reversibility of renal damage in a cohort of HIV-infected patients receiving tenofovir-containing antiretroviral therapy
. Antiviral Res
38. Jose S, Hamzah L, Campbell LJ, Hill T, Fisher M, Leen C, et al. Incomplete reversibility of estimated glomerular filtration rate decline following tenofovir disoproxil fumarate exposure
. J Infect Dis
39. Post FA, Wyatt CM, Mocroft A. Biomarkers of impaired renal function
. Curr Opin HIV AIDS