C

Prospective study of rena

l function in HIV-infectedpediatric patients receiving tenofovir-containing

HAART regimens

Pere Soler-Palacına,M, Susana Melendoa,M, Antoni Noguera-Julianb,

Claudia Fortunyb, Marıa L. Navarroc, Marıa J. Melladod,

Lourdes Garciae, Sonia Urionaf, Andrea Martın-Naldaa

and Concepcio Figuerasa

opyright © L

aPediatric InfectioPediatric DepartmGregorio MaranonePediatric DepartmBarcelona, Spain.

Correspondence toHospital, Passeig

Tel: +34 93 489 3�

These two autho

Received: 1 July 2

DOI:10.1097/QAD

ISS

Aim: To describe the impact of tenofovir disoproxil fumarate (TDF) use on renalfunction in HIV-infected pediatric patients.

Design: It is a prospective, multicenter study. The setting consisted of five third-levelpediatric hospitals in Spain. The study was conducted on patients aged 18 years andyounger who had received TDF for at least 6 months. The intervention was based on thestudy of renal function parameters by urine and serum analyses. The main outcomemeasures were renal function results following at least 6 months of TDF therapy.

Results: Forty patients were included (32 were white and 26 were diagnosed withAIDS). Median (range) duration of TDF treatment was 77 months (16–143). There wereno significant changes in the estimated creatinine clearance. Urine osmolality wasabnormal in eight of 37 patients, a decrease in tubular phosphate absorption wasdocumented in 28 of 38 patients, and 33 of 37 patients had proteinuria. A statisticallysignificant decrease in serum phosphate and potassium concentrations was observedduring treatment (P¼0.005 and P¼0.003, respectively), as well as a significantrelationship between final phosphate concentration and tubular phosphate absorption(P¼0.010). A negative correlation was found between phosphate concentration andtime on TDF.

Conclusions: TDF use showed a significant association with renal tubular dysfunctionin HIV-infected pediatric patients. Periodic assessment of tubular function may beadvisable in the follow-up of this population.

� 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

AIDS 2011, 25:171–176

Keywords: kidney, pediatrics, reverse transcriptase inhibitors, tenofovirdisoproxil fumarate, toxicity

Introduction

Tenofovir disoproxil fumarate (TDF) is the firstnucleotide reverse transcriptase inhibitor approved by

ippincott Williams & Wilkins. Unauth

us Diseases and Immunodeficiencies Unit, Vallent, Sant Joan de Deu Hospital-Universitat de BUniversity General Hospital, dPediatric Infectioent, Hospital de Mataro, Mataro, and fPreventiv

Pere Soler-Palacin, MD, Pediatric Infectious DisVall d’Hebron 119-129, 08035 Barcelona, Spain

140; fax: +34 93 489 3039; e-mail: psoler@vhe

rs contributed equally to this work.

010; revised: 6 September 2010; accepted: 23

.0b013e328340fdca

N 0269-9370 Q 2011 Wolters Kluwer He

the Food and Drug Administration (FDA) and theEuropean Medicines Agency for the treatment of HIVinfection in adults and has been a first-line antiretroviraldrug since 2001 [1]. On the basis of the results of the

orized reproduction of this article is prohibited.

d’Hebron University Hospital, bInfectious Diseases Unit,arcelona, Barcelona, cPediatric Infectious Diseases Unit,us and Tropical Diseases Unit, Carlos III Hospital, Madrid,e Medicine Department, Vall d’Hebron University Hospital,

eases and Immunodeficiencies Unit, Vall d’Hebron University.

bron.net, 34660psp@comb.cat

September 2010.

alth | Lippincott Williams & Wilkins 171

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172 AIDS 2011, Vol 25 No 2

GS-US-104-0321 study, which will be published at theend of this year, TDF recently received FDA approval foruse in pediatric patients aged 12–18 years and weighingmore than 35 kg. Moreover, it has been used as salvagetherapy in pediatric patients for several years, and variousreports support the safety and efficacy of the drug in thispopulation [2–4]. In the pediatric cohort of the SpanishAIDS Research Network (CoRISpe, Cohorte Pediatricade la Red de Investigacion de SIDA), which includesvirtually all HIV-infected children in Spain, 87 of the 621patients included (14%) are receiving or have receivedTDF at some time (unpublished data).

Since the introduction of HAART and with the advancesin our understanding of the disease, survival in HIV-infected children has considerably improved [5]. This hasled to lengthier exposure to antiretroviral treatments and anincrease in secondary complications, among which is renaltoxicity involvement. The spectrum of renal disease in HIVpatients has changed in recent years and there areindications of a more prominent role for drug-relatedadverse effects than nephropathy caused by the virus itself[6–8]. The antiretroviral agents most commonly associatedwith renal toxicity are lopinavir (LPV), ritonavir (RTV)[9], didanosine (ddI) [10], and, more recently, TDF [11].

Various randomized clinical trials in adults have describeda good safety profile for TDF, and very few cases of renalalterations [12–16]. Nonetheless, another randomizedstudy has reported cases of tubular dysfunction [17] andcohort studies have described renal dysfunction, tubulardysfunction, and diabetes insipidus associated with the useof this drug [12–16]. The importance of renal toxicitycaused by TDF is further underlined by reports suggestingthat the effects may not be reversible when the drug isdiscontinued [18]. The pathogenesis of tubular involve-ment by TDF is unknown. Some authors citeinterference with a transporter protein of the tubularepithelial cells, whereas others propose a mechanism ofmitochondrial toxicity, as occurs with ddI, or a possiblegenetic predisposition [19–21]. A recent report hasprovided evidence of an association between TDF-related renal toxicity and elevated plasma concentrationsof the drug [22].

Little is known about TDF toxicity in pediatric patients.Two randomized studies in children receiving TDF aspart of their HAART regimens determined a favorablesafety profile for the drug [3,4], whereas in some pediatriccohort studies, cases of renal toxicity have been described,mainly affecting the renal tubules [2,23–25]. A recentcase–control study, in which serum renal functionmarkers were determined in patients receiving TDF,suggested a possible association between the use of thisdrug and development of hypophosphatemia. On thebasis of these results, the authors proposed tubularfunction monitoring in children receiving long-termTDF therapy [8].

pyright © Lippincott Williams & Wilkins. Unautho

The present prospective, multicenter study investigatespossible TDF-related kidney damage in HIV-infectedpediatric patients in Spain, by assessment of renal functionmarkers in serum and urine.

Patients and methods

A multicenter cohort study was conducted between2007 and 2009, with retrospective and prospective datacollection in a two-phase design. The study was approvedby the Ethics Committee of the coordinating center (Valld’Hebron University Hospital, Barcelona, Spain) andinformed consent for participation was obtained frompatients and/or their tutors. Pediatric patients receivingTDF as part of their antiretroviral treatment and followedup in the participating centers were included. In the firstphase, the patients’ medical records were reviewed andthe following information was collected: demographicdata, renal function results at the time TDF treatmentwas started, and concomitant use of other potentiallynephrotoxic agents (indinavir, LPV/RTV, ddI, ampho-tericin, foscarnet, and vancomycin). TDF dosing wasadjusted to body weight in all cases. Nineteen patientsreceived TDF in a fixed combination with emtricitabine(Truvada; Gilead Sciences Inc., Foster City, California,USA) and one patient was given TDF in a fixedcombination with emtricitabine and efavirenz (Atripla;Bristol-Myers Squibb, New York, New York, USA andGilead Sciences Inc.).

A second phase was conducted prospectively during thestudy period. After at least 6 months of TDF treatment,24-h urine specimens were obtained and renal functionwas determined in serum and urine, including tubularfunction testing and 4-h urine osmolality testing. Inaddition, kidney and bladder ultrasound was performed inall cases to evaluate morphological alterations.

Renal function alterations were defined as any of thefollowing situations: diuresis less than 1 ml/kg per h,creatinine clearance (CrCl) (calculated with the Schwartzformula [26,27]) below the normal values by age and sexfor the Spanish pediatric population [28], fractionalsodium excretion more than 2, tubular phosphatereabsorption (TPR) less than 90% or presence ofsignificant urinary calcium or uric acid levels, proteinuriamore than 4 mg/m2 per h, urine osmolality abnormalities(defined as less than 800 mOsm/kg after restricted fluidintake), or renal ultrasound alterations. The adverseeffects encountered were evaluated with the Division ofAIDS (DAIDS) Adverse Events Grading Table (http://rsc.tech-res.com/safetyandpharmacovigilance).

In the descriptive analysis of the data, categorical variablesare expressed as the number and percentage, andcontinuous variables as the median and range. The

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Renal safety of tenofovir in children Soler-Palacın et al. 173

presence of adverse renal effects (yes/no) was thedependent variable in the bivariate analysis. The x2 orFisher’s exact test was used to determine relationshipswith the independent categorical variables, and theMann–Whitney U test with continuous variables.Associations between the main variable and independentvariables were calculated. Statistical analyses wereperformed with SPSS 13.0 (IBM, Chicago, Illinois,USA). Significance was set at a value of 0.05 or less.

Results

Forty patients aged 18 years or less were included in thestudy. There were no patients lost to follow-up during thestudy. The patients’ baseline characteristics are shown inTable 1. Median age was 12.5 years (range 8–17 years) atthe start of TDF-containing HAARTand 15 years (range11–20 years) when renal function was evaluated. Twopatients had previous kidney disease (congenital poly-cystic disease and left congenital hydronephrosis that hadspontaneously resolved at the time of the study).

None of the patients presented serum creatinineconcentrations higher than 1 mg/dl at baseline and onlytwo showed a CrCl level lower than normal for their age.Nine patients had received prior nephrotoxic drugs (mostcommonly indinavir, with five cases).

Median duration of TDF treatment was 77 months(range 16–143). Ten patients received other nephrotoxicantiretroviral drugs together with TDF (LPV/RTV,n¼ 7, and ddI, n¼ 3). The ddI–TDF combination wasgiven before 2005 in all patients receiving this treatment.

In the renal function study after at least 6 months of TDFtherapy, a decrease in CrCl values (median decrease of

opyright © Lippincott Williams & Wilkins. Unauth

Table 1. Baseline characteristics of the study patients.

Total number (N¼40 patients)

Female/male 21/19Median age 12.5 years (range 8–17 years)Median BMI 20Race: white/black/others 32/4/4CDC clinical category A/B/C 9/13/18CDC immunological category 1/2/3 7/11/22Diagnosed with AIDS 26#

HCV coinfection 6Previous renal disease 2Previous nephrotoxic therapy 9Previous ARV treatment regimens:

None/1–2 3/63–5/6–10 12/17>10 2

Serum creatinine >1 mg/dl 0Abnormal CrCl 2

ARV, antiretroviral; CDC, Centers for Disease Control; CrCl, creati-nine clearance; HCV, hepatitis C virus.#Clinical criteria in 18 and immunological criteria in 8.

16.5 mg/ml, range 1–100) was observed in 18 patients.Nonetheless, in only four of these patients, CrCl at theend of the study was below normal values (previouslydocumented in two patients at the beginning of thestudy).

In addition, a TPR decrease was found in 28 of 38patients [74%, 95% confidence interval (CI) 56.9–86.6%], proteinuria was seen in 33 patients (89%, 95% CI75–97%), of whom 10 had proteinuria in the nephroticrange, and urine osmolality alterations were documentedin eight of the 37 patients studied (22%) (Table 2). Noneof the patients presented pathologic calciuria and fivepatients had increased urinary uric acid levels. Only thepatient with congenital polycystic disease presentedabnormal sonographic findings (increased size andechogenicity of the kidneys). One patient died duringthe study period of causes unrelated to TDF treatment orrenal dysfunction (cytomegalovirus disease resistant toantiviral therapy).

In the study of risk factors associated with glomerularfiltration alterations, there were no significant differencesregarding the patients’ baseline characteristics, includinghepatitis C virus infection and other concomitantpathologies.

A significant increase in serum creatinine concentrationbetween the pretreatment and the final determination(P¼ 0.001) was observed and alterations in urineosmolality occurred more often in patients who hadreceived prior nephrotoxic drugs [P¼ 0.049 and relativerisk (RR) 6.25, 1–35].

A statistically significant decrease in serum phosphate andpotassium concentrations was seen along the durationof treatment (P¼ 0.005 and P¼ 0.003, respectively)(Table 3), and six patients presented DAIDS grade 1 or 2serum phosphate decrease. There was no relationshipbetween phosphate concentration at completion of thestudy and the baseline characteristics or baselineglomerular involvement. In contrast, an association wasfound between final serum phosphate values and TPRalteration (P¼ 0.010), together with a negative corre-lation between serum phosphate concentration and timeon TDF treatment (r¼�0.48, P¼ 0.013) (Fig. 1). Thislatter association was not seen for serum potassiumconcentration (P¼ 0.08).

Proteinuria and TPR alteration were not related withsignificant baseline immunosuppresion (P¼ 0.61 andP¼ 0.73, respectively) nor low BMI (P¼ 0.60 andP¼ 0.30, respectively).

Patients who additionally received LPV/RTV or ddI didnot exhibit more pronounced CrCl decreases or higherserum creatinine levels. There was, however, a statisticallysignificant urine osmolality alteration in patients receiving

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174 AIDS 2011, Vol 25 No 2

Table 2. Renal function parameters in the study patients.

Affected patients/totalpatients studied

Percentage over totalpatients studied (%)

CrCl below normal values at the end of the study 4/38M 10TPR alteration 28/38 74Moderate-severe proteinuria 33 (23–10)/37 89 (62–27)FENa alteration 1/35 3Urine osmolarity alteration 8/37 22

CrCl, creatinine clearance; FENa, fractional sodium excretion; TPR, tubular phosphate reabsorption.MAlready documented in two patients at the beginning of the study.

LPV/RTV together with TDF (P¼ 0.027 and RR 8.7,1.4–54). All patients receiving LPV/RTVor ddI showedmoderate to severe proteinuria, as well as a lower TPR(Fig. 2).

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DF

Discussion

The use of TDF is not unusual in the pediatric age,particularly in the adolescent population. Currently inSpain, 14% of patients in the CoRISpe cohort havereceived TDF at some time point as a part of theirHAART regimens (unpublished data). The demographicand clinical characteristics of the patients included in ourstudy are similar to those of the CoRISpe patients whoreceived TDF, as well as to those included in previousstudies [2,4,8], that is, mainly, adolescents who were givenTDF as part of a salvage therapy. Thus, it is likely that thestudy results would be applicable to the overall populationof pediatric patients receiving this drug. The findings ofconsiderable tubular dysfunction observed in our patientsdo not differ from the results of other studies in childrenassessing renal toxicity associated with TDF use [2,8,25].

It has been well demonstrated that the specimen of choiceto determine the existence of tubular proteinuria is 24-hurine [6,13,29], as we used in this study. Other, simplermethods, including urine reagent strips or the urinaryprotein/creatinine ratio, used by other authors [30] areless suitable for this purpose.

Moderate (>4 mg/m2 per h) or severe (>40 mg/m2 perh) proteinuria was detected in 78% of the patients studied,

pyright © Lippincott Williams & Wilkins. Unautho

Table 3. Serum concentrations of potassium, phosphate, and sodiumat baseline and completion of the study.

VariablesBaseline End

P (Student’s t-test)Mean (range) Mean (range)

Potassium (K) 4.1 (3.7–5.0) 3.9 (3–4.7) 0.003Phosphate (P) 4.5 (3.1–5.8) 4.1 (2.4–5.9) 0.005Sodium (Na) 140 (134–146) 139 (134–144) 0.126

Normal values: serum K concentration, 2.5–5.0 mmol/l; serumNa concentration, 135–145 mmol/l; Serum P concentration, 4.0–7.0 mg/dl.

suggesting some degree of glomerular dysfunction inmost severe cases. The fact that proteinuria was notmeasured at baseline in our study precludes establishmentof a causal relationship with TDF use. Nonetheless, theprogressive tubular dysfunction observed followinginitiation of TDF suggests an etiological role for thedrug. The association between proteinuria and TDF usein HIV-infected patients has not been well established. Inthis regard, a percentage of proteinuria similar to thatrecorded in our cohort has been described for adult HIV-infected patients, although no relationship with thedifferent antiretroviral regimens could be established [29].In other studies, however, TDF use has been associatedwith proteinuria in both adults and children [6,31,32].Papaleo et al. [31] reported that more than a quarter ofpatients receiving TDF presented elevated urinary levelsof b-2 microglobulin, which normalized upon with-drawal of the drug.

With regard to serum and urinary phosphate concen-trations, TPR abnormalities were seen in 90% of patientsand six of them showed a DAIDS grade 1 or 2 serumphosphate decrease. Moreover, serum phosphate altera-tions were significantly related to both TPR changes and

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6,05,04,03,02,0

4,00

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Serum phosphate concentration

Fig. 1. Lineal correlation between serum phosphate concen-tration and time on tenofovir disoproxil fumarate treatment(r U S0.48, P U 0.013). TDF, tenofovir disoproxil fumarate.

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Renal safety of tenofovir in children Soler-Palacın et al. 175

Fig. 2. Renal abnormalities in patients receiving combi-nation therapy with didanosine or lopinavir/ritonavir withtenofovir disoproxil fumarate. ddI, didanosine; LPV, lopina-vir; RTV, ritonavir.

time on TDF treatment. In the study by Judd et al. [8], adifference was seen in the incidence of hypophos-phatemia (DAIDS grade 2) between patients on TDFand those who had never received this drug. Along thissame line, Izzedine et al. suggested that hypophos-phatemia (as well as glucosuria in the absence ofhyperglycemia) would be a good marker of tubulartoxicity due to TDF [15]. In contrast, other authorscontend that moderate, asymptomatic hypophosphatemiais normal in adult HIV-infected patients regardless of theHAART they receive [11,33]. Nonetheless, these studieswere performed in adults and follow-up lasted less than1 year, factors that could explain the differences withrespect to our study that had a follow-up of around6.5 years.

There were no cases of Fanconi syndrome in our series,an uncommon complication recently reported in patientsreceiving TDF [23,34].

It has been described that TDF-related renal toxicity mayincrease when the drug is combined with otherantiretroviral drugs [23], particularly with LPV/RTVor ddI. Most patients in our cohort had been treated withseveral antiretroviral regimens, although few of themreceived TDF combined with LPV/RTV or ddI. TheTDF–LPV/RTV combination was associated withmoderate to severe proteinuria and TPR decrease,although the differences with respect to the remainingpatients were not significant, possibly because of the smallsample size. A significant association was found betweenurine osmolality alterations and combined use of TDFand LPV/RTV. This finding may be related to an increasein plasma TDF resulting from pharmacokinetic inter-actions between the two antiretroviral drugs [23,35], afactor that was not investigated in our study.

Considering that the peak in bone mineral densityoccurring in adolescence is inversely related with the riskof osteopenia, osteoporosis, and bone fracture inadulthood [36–37], the increased incidence of bonepathology in HIV-infected patients [38] supports the ideathat monitoring calcium–phosphate metabolism in HIV-

opyright © Lippincott Williams & Wilkins. Unauth

infected children and adolescents is of particular interest.Furthermore, some authors have found that TDF use is anindependent risk factor for developing bone mineral loss[39]. In an experimental animal study, Van Rompay et al.[40] demonstrated an association between prolonged,high-dose TDF administration and hypophosphatemiaand development of osteomalacia.

The main limitation of our study is the relatively smallsample size, although the comparability of the patientsincluded with those receiving TDF in the CoRISpecohort and other pediatric studies evaluating TDF-associated renal toxicity confers greater validity to theresults obtained. In addition, because baseline evaluationof tubular function was not performed, it was not possibleto establish a causal relationship in the results found. Inany case, the documentation of significant proteinuria in ahigh percentage of patients and the correlation betweenphosphate levels and tubular dysfunction, as well as theoptimum sample studied (24-h urine), lead us to suggestthat TDF played an important role in the renalalterations described.

In conclusion, this is the first study prospectively assessingrenal function in depth, including analysis of tubularfunction, in pediatric patients undergoing long-termTDF treatment. On the basis of the results obtained, webelieve that periodic monitoring of tubular functionshould be included in the routine follow-up of thesepatients. Further investigation is needed to determine thecontribution of TDF to alterations in calcium–phosphatemetabolism and its potential association with bonemetabolism alterations.

Acknowledgements

This study was funded in part by the AIDS ResearchNetwork (RIS, Red de Investigacion en SIDA) and theFoundation for AIDS Research and Prevention in Spain(FIPSE, Fundacion para la Investigacion y la Prevenciondel SIDA en Espana; 240813/09).

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