renal toxicity associated with antiretroviral therapy

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HIV Clin Trials 2012;13(4):189211 2012 Thomas Land Publishers, Inc.www.thomasland.com

doi: 10.1310/hct1304-189

Address for correspondence: Dr. Leonardo Calza, Sect ion of Infectious Diseases, S. Orsola-Malpighi Hospital, Alma MaterStudiorum University of Bologna, via G. Massarenti 11, I-40138Bologna, Italy; phone: +39 051 6363355; fax: +39 051 343500;e-mail: [email protected]

Renal Toxicity Associated With Antiretroviral Therapy

Leonardo CalzaDepartment of Internal Medicine, Geriatrics and Nephrologic Diseases, Section of Infectious Diseases,

S.Orsola-Malpighi Hospital, Alma Mater Studiorum University of Bologna, Italy

Renal disease is becoming an increasingly prevalent comorbidity in patients withhuman immunodeciency virus (HIV) infection. The increase in life expectancy fol-lowing the introduction of highly active antiretroviral therapy (HAART) and the long-term development of metabolic complications (such as diabetes and dyslipidaemia),hypertension, and vascular diseases can contribute to the increasing frequencyin the recognition of renal impairment in HIV-infected patients. Some antiretrovi-ral agents, and particularly tenofovir, have been associated with nephrotoxic drugeffects, including decline in glomerular ltration rate, proximal tubular damage, andacute kidney injury. The occurrence of clinically evident renal toxicity in patientstreated with HAART seems to be very low, but glomerular or tubular subclinicaldysfunction may occur more frequently. Therefore, careful clinical and laboratorymonitoring for the early recognition of renal abnormalities is recommended for allsubjects receiving antiretroviral treatment. In this article, the current knowledgeabout the nephrotoxic effects of antiretroviral agents has been reviewed, and analgorithm for screening and management of HAART-related kidney disease is pro-posed in the light of the most recent clinical studies and international guidelines.Key words: antiretroviral therapy, glomerular dysfunction, nephrotoxicity, screening,tenofovir, tubular dysfunction

S ince the introduction of highly activeantiretroviral therapy (HAART) has led to adramatic decline in morbidity and mortalityassociated with human immunodeciency virus-1

(HIV-1) infection and acquired immune deciencysyndrome (AIDS), several complications of long-standing infection and long-term treatmenthave been recognized with increasing frequency.

These noninfectious comorbidities include avariety of renal diseases, ranging from subclinicalproteinuria to acute renal failure, which may descendfrom both nephrotoxic effects of antiretroviralagents and kidney infection due to HIV itself. Atthe same time, prolonged survival and prematureaging of HIV-positive patients increase the risk of metabolic and inammatory abnormalities (such as

dyslipidaemia, diabetes mellitus, and endothelialdysfunction) that, in turn, may contribute tovascular disease and decline in renal function.

On the other hand, the introduction of potentantiretroviral regimens leads to a persistentviral suppression correlated with an improvingglomerular ltration rate (GFR) and a decliningincidence of chronic kidney diseases in theHIV-positive population. Positive effects of HAART on renal function have been observed inseveral cohort studies, whereas uncontrolled viral

replication and low CD4 lymphocyte count werefound to be signicant predictors of kidney disease.

Consequently, the long-term effects of antiretroviraltherapy on the kidneys are debated still today. This

review focuses on the favorable and damaging effectsof antiretroviral agents on renal function and suggestsan algorithm for early recognition and appropriatemanagement of drug-related nephrotoxicity.

FAVORABLE EFFECTS OF HAART ON RENALFUNCTION

The introduction of combination antiretroviraltherapy in clinical practice has been associatedwith an improvement in GFR and a reducedincidence of chronic kidney disease, mostly in


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The occurrence of severe glomerular impairmentwas infrequent (


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Isolated reports of renal injury have been pub-lished for nearly all of the currently availableantiretroviral agents, but these cases are veryuncommon and a direct causal relationship remainsuncertain in most reports. The occurrence of vari-ous kinds of nephrotoxicity has been reported inpatients treated with nucleoside reverse transcrip-tase inhibitors (NRTIs), non-nucleoside reversetranscriptase inhibitors (NNRTIs), or proteaseinhibitors (PIs), but the pathogenetic mechanismof renal damage remains usually unknown. Only3 antiretroviral agents have a well-establishedassociation with direct renal toxicity sustained byseveral case reports and cohort studies, namelytenofovir, indinavir, and atazanavir. 2,8,10-14

Most drugs and their metabolites are excretedthrough the kidneys by glomerular ltration and

tubular secretion. Particularly, drug and toxinexcretion usually involves the proximal tubulewhere there is a high rate of blood ow, and con-sequently this part of the nephron is at increasedrisk of developing drug-related injury. Moreover,proximal tubule dysfunction may be caused bya crystal-induced obstruction or by severe mito-chondrial abnormalities induced by specic PIs orNRTIs. Otherwise, renal toxicity may occur in thecontext of an idiopathic, systemic hypersensitivityreaction. Finally, chronic metabolic complications(such as diabetes mellitus and dyslipidaemia)associated with life-long antiretroviral treatmentmight increase the risk of vascular chronic renaldisease. 10,12,14

The most common nephrotoxic effects of HAARTare summarized in Table 1 .

Table 1 . Potential nephrotoxic effects of antiretroviral agents 1-3,7,11

Class of nephropathy andpathological lesions

Potential pathogeneticmechanism

Clinical manifestation Drugs potentially involved

Glomerular dysfunction Unknown Reduced GFR, CKD Tenofovir, didanosine

Proximal tubulardysfunction

Mitochondrial cytopathy withimpaired mechanisms of cellmembrane transport

Proteinuria,hypophosphatemia,Fanconi syndrome,diabetes insipidus,

AKI

Tenofovir, didanosine,abacavir, ritonavir-boosted PIs

Acute tubular necrosis Mitochondrial cytopathy withlactic acidosis

Renal tubular acidosis Stavudine, didanosine,lamivudine

Acute interstitial nephritis Hypersensitivity reaction,intratubular crystaldeposition

Hematuria,hypertension, AKI

Abacavir, efavirenz,atazanavir, indinavir

Obstructive uropathy Intratubular crystal deposition Nephrolithiasis andrenal colic, ankpain, crystalluria,hematuria, AKI

Indinavir, atazanavir(exceptionally other PIs)

Myoglobinuric pigmentnephropathy

Rhabdomyolysis AKI Zidovudine, didanosine

Vascular chronic disease Metabolic alterations(dyslipidemia, diabetesmellitus) and prematureatherosclerosis

Reduced GFR, CKD Stavudine, didanosine,ritonavir-boosted PIs

Note: CKD = chronic kidney disease; AKI = acute kidney injury; GFR = glomerular ltration rate; PIs = protease inhibitors.

RENAL T OXICITY ASSOCIATED W ITH ART C ALZA 191


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TENOFOVIR AND RENAL TOXICITY

Tenofovir is an acyclic nucleotide analoguereverse transcriptase inhibitor, which shows high

antiviral activity against both HIV and hepatitis Bvirus. Overall, tenofovir has a good safety proleand is recommended for the rst-line antiretrovi-ral therapy by the US Department of Health andHuman Services 15 and the European AIDS ClinicalSociety Guidelines. 16 It is the most widely usedantiretroviral drug worldwide.

Although both in vitro and in vivo studies andclinical trials support the renal safety of tenofovir,this drug is structurally similar to nephrotoxicagents adefovir and cidofovir, and its clinical useis associated with a low, albeit signicant, risk of

kidney toxicity. Consequently, the present concernabout HAART-induced nephrotoxicity is essen-tially focused on tenofovir. 17,18

A number of studies have assessed the rela-tionship between tenofovir exposure and renaldysfunction, but the literature is nonstandardized,without diagnostic specicity for the cause of renalabnormalities, and retrospective and prospectivestudies evaluating incidence and prevalence of this complication are often not comparable. How-ever, several case reports, retrospective series, andprospective cohort studies have found evidence of

potential nephrotoxic effects associated with thetenofovir use. These renal complications include both glomerular damage (expressed by reducedGFR) and proximal tubular dysfunction (includingproteinuria, calcium and phosphorus dysregula-tion, Fanconi syndrome, reduced bone mineraldensity, and diabetes insipidus), which may beassociated with acute kidney injury or chronic kid-ney disease. 2,14,17,18

A retrospective review of the US Food and DrugAdministration (FDA) Adverse Event ReportingSystem from 2001 through 2006 was performed to

evaluate temporal trends and risk factors associatedwith Fanconi syndrome in HIV-infected patientstreated with tenofovir. This large case seriesincluded 164 subjects who met the case denition forFanconi syndrome: 83% of the patients were treatedwith tenofovir and PIs, 74% of the total received aritonavir-boosted PI, and 34% of the subjects weretreated with didanosine and a ritonavir-boostedPI. Fractures and requirement for dialysis wereuncommon (2% for each adverse event); nearly half of the total subjects were hospitalized. 19

A retrospective cohort analysis in the KaiserPermanente organization from 2002 to 2005compared renal function among HIV-positiveantiretroviral-nave patients starting a tenofovir-containing regimen (964 patients) or tenofovir-sparing regimens (683). Renal function assessmentincluded evaluation of changes in serum creatinine(estimated glomerular filtration rate [eGFR],calculated using the 4-variable Modication of Diet in Renal Disease [MDRD] formula 20) and thedevelopment of proximal tubular dysfunction(diagnosed with more than 2 of the following:proteinuria, glycosuria with normal glycemia,hypophosphatemia or phosphaturia, serumacidosis, hypokaliemia, and hypouricemia),during a 104-week follow-up. Overall, tenofovir-exposed patients had a significantly greaterdecline in eGFR than tenofovir-unexposed ones(7.6 mL/min/1.73m 2 relative to tenofovir-sparing; P < .001). Similarly, tenofovir recipientshad a signicantly higher incidence of proximaltubulopathy over time (at 104 weeks hazardratio [HR], 5.23; P = .0004), and a greater risk of treatment discontinuation (HR, 1.21; P = .02).21

The EuroSIDA cohort study evaluated theincidence of chronic kidney disease among 6,843HIV-infected persons with at least 3 serum cre-atinine measurements and corresponding body

weight measurements from 2004 to 2008. Chronickidney disease was dened as either conrmed(3 months apart) eGFR 60 mL/min per 1.73 m 2 (calculated using the Cockcroft-Gault [CG] for-mula 22) for patients with baseline eGFR >60 mL/min per 1.73 m 2 or conrmed 25% decline ineGFR for patients with baseline eGFR 60 mL/min per 1.73 m 2. Overall, 225 (3.3%) patients pro-gressed to chronic kidney disease during 21,482person-years follow-up, with an incidence of 1.05per 100 person-years follow-up. After adjustmentfor traditional predictors of chronic nephropathy,

increasing cumulative exposure to tenofovir wasassociated with a signicantly increased rate of chronic kidney disease. The increase in risk of nephropathy was also true for a higher exposure toindinavir and atazanavir, whereas the results forlopinavir/ritonavir were less clear. 23

A cross-sectional survey conducted in the Frenchhospital-based Aquitaine Cohort did estimatethe prevalence of renal impairment among 2,588adult HIV-infected patients. The clearance of creatinine was calculated using the CG formula,

192 HIV CLINICAL T RIALS 13/4 J ULY -AUG 2012


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and 4 stages of renal impairment were dened,ranging from mild impairment (clearance between60 and 90 mL min) to end-stage disease (clearance


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events (including clinically evident renal toxicity)and premature study discontinuation rate due toadverse events were comparable in both groups. 30 A randomized, controlled, open-label study evalu-ated efcacy and safety of a simplication strat-egy to tenofovir/emtricitabine/efavirenz versusunchanged baseline regimen in 300 adult patientson stable antiretroviral therapy with persistentlysuppressed plasma HIV RNA. At week 48, dis-continuation rates were similar, and eGFR (MDRDequation) remained unchanged in both arms. 31

In the randomized, open-label, multicenterASSERT study, efcacy and safety of abacavir-lamivudine versus tenofovir-emtricitabine, eachadministered with efavirenz, were assessed in 385antiretroviral-nave patients followed-up for 48weeks. The adverse event rates and the changesin eGFR (MDRD formula) from baseline valueswere similar between arms, but tenofovir-treatedsubjects showed a signicantly higher incidence of tubular dysfunction. 32

The BICOMBO study randomly assigned 333HIV-infected subjects on lamivudine-containingtriple regimen with virological suppression toswitch their nucleosides to either abacavir/lami-vudine or tenofovir/emtricitabine. At week 48,no signicant difference in eGFR (CG equation)changes was detected between abacavir recipients

and tenofovir recipients.33

The AIDS Clinical Trials Group Study A5202 is arandomized equivalence trial comparing efcacyand safety for atazanavir/ritonavir with efavirenz,each in association with tenofovir/emtricitabineor abacavir/lamivudine, in 1,857 antiretroviral-nave patients. Incidence of Fanconi syndrome,toxic nephropathy, proteinuria, or renal failurewas comparable across the 4 groups at weeks 48and 96. Similarly, changes from baseline in calcu-lated creatinine clearance were similar in subjectstreated with tenofovir/emtricitabine or abacavir/

lamivudine, but reduction in calculated creatinineclearance at both weeks 48 and 96 was signicantlyhigher in recipients of tenofovir/emtricitabine plusatazanavir/ritonavir compared with those receiv-ing tenofovir/emtricitabine plus efavirenz. 34

Finally, a recent meta-analysis showed thatHIV-infected patients treated with tenofovir hada greater relative risk of renal disease (dened asacute or chronic reduced renal function with eGFR60 mL/min/1.73 m 2) than those treated with anon-tenofovir therapy (RR, 1.56; 95% CI, 0.83-2.93). 13

TENOFOVIR AND SUBCLINICAL TUBULARDYSFUNCTION

The renal toxicity associated with tenofovir use

more frequently involves the proximal tubule inthe absence of signicantly impaired glomerularfunction, and more evident data result from stud-ies investigating subclinical proximal tubulopathy.However, it is uncertain still today whether routinelaboratory tests for tubular dysfunction (such as spotproteinuria, glycosuria, urine protein-to-creatinineratio [PCR] or albumin-to-creatinine ratio [ACR]),hyperphosphaturia, or hyperuricosuria) are suf-ciently sensitive screening tests to detect subclini-cal tubular damage. More recently, other biologicalmarkers of proximal tubulopathy have been con-

sidered, including low molecular weight proteins(LMWPs), which are usually ltered through theglomerulus and almost entirely reabsorbed by theproximal tubule. An increased urinary excretionof these small proteins indicates either tubulardysfunction or tubular injury, and their urinaryconcentration is a measure of the severity of tubu-lar damage. These LMWPs include retinol-bindingprotein (RBP), -2-microglobulin, and neutrophilgelatinase-associated lipocalin (NGAL). Further-more, N-acetyl- -D-glucosaminidase (NAG) is ahigh molecular weight lysosomal enzyme local-ized in tubular epithelial cells, and increased urineamounts of NAG are indicative of a specic tubularcell damage. 35

In the randomized, open-label ASSERT trial,urinary excretion of RBP and -2-microglobulinincreased significantly more in the tenofovir/emtricitabine arm (+50% and +24%, respectively)compared with the abacavir/lamivudine arm (nochange and -47%, respectively; P < .0001).32

A cross-sectional study enrolled 99 HIV-infectedpatients with serum creatinine


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and -2-microglobulinuria) in 284 HIV-positivepatients allocated in 3 groups: patients on HAARTreceiving tenofovir, patients on HAART neverexposed to tenofovir, and antiretroviral-navepatients. No signicant differences in creatinineclearance were observed across the 3 groups, butin a multivariate analysis the only independentpredictors of tubular dysfunction were tenofoviruse and older age. 37

Among 40 patients treated with tenofovirand 23 patients treated with other NRTIs, urine-2-microglobulin, percentage tubular reabsorp-tion of phosphate, alkaline phosphatase, serumcreatinine, and eGFR were prospectively evalu-ated for 96 weeks. In subjects receiving tenofovir,median -2-microglobulin rose from 188 g/L at baseline to 555 g/L at week 96, median percent-age tubular reabsorption of phosphate declinedfrom 94% at baseline to 90% at week 96, andmedian alkaline phosphatase ratio compared with baseline increased from 1 to 1.278 at week 96, whilemedian eGFR declined minimally but signicantlyin tenofovir recipients. Overall, prolonged teno-fovir treatment caused a progressive subclinicaltubular damage as well as a modest reduction inthe glomerular function. 38

A cross-sectional analysis in a hospital outpa-tient-based cohort has investigated bone mineral

density, bone metabolism, and renal function in153 adult HIV-infected patients. The eGFR wascalculated by CG formula, and proximal tubulardysfunction was diagnosed by the presence of 2of the following abnormalities: renal tubular phos-phate loss, increased urine ACR, glycosuria withnormal glycaemia, and a reduced plasma bicarbon-ate level. The presence of proximal tubulopathywas signicantly associated with a longer durationof HIV infection and a longer exposure to tenofoviror boosted PIs. Moreover, PI therapy was signi-cantly associated with low bone mineral density in

multivariable analysis.39

Urinary -2-microglobulin levels were mea-sured in a cross-sectional study involving 70subjects treated with tenofovir and 90 subjects onother antiretroviral therapy who had never beenexposed to tenofovir. The mean urine concentra-tion of -2-microglobulin was signicantly higherin tenofovir-treated subjects than in tenofovir-untreated ones, while no signicant differencewas detected in eGFR (CG equation). Multivariateanalysis showed that a concomitant therapy with

lopinavir/ritonavir and a lower body weight wereassociated with increased urine -2-microglobulinlevels. 40 In the same way, patients with Fanconisyndrome occurring during the tenofovir treat-ment show very high urinary levels of RBP andcystatin C, and these biomarkers may prove to beuseful to early recognize patients with Fanconisyndrome. 41,42

Even though many observational studies dem-onstrate a signicant association between tenofovirexposure and subclinical tubular dysfunction, theclinical long-term consequences of this isolatedtubular damage remain unclear. Particularly, it isunknown today whether tubular abnormalities aresignicant predictors of subsequent Fanconi syn-drome, acute or chronic renal failure, and reduced bone mineral density.

Certainly, the proximal renal tubular dysfunc-tion can result in excessive renal phosphate and bicarbonate losses, and it might promote a decreasein bone mineral density through renal phosphatewasting. In the above-mentioned cross-sectionalanalysis involving a hospital outpatient-basedcohort, serum levels of markers associated withincreased bone turnover (such as alkaline phos-phatase, osteocalcin, and urinary hydroxyprolineexcretion) were signicantly higher in patientstreated with tenofovir, suggesting increases in both

osteoblast and osteoclast activity.39

In a retrospec-tive case series study assessing 30 HIV-infectedsubjects with foot fractures, more foot fractureswere diagnosed in tenofovir-treated subjects thanin non-tenofovir-treated subjects, and osteoporosiswas signicantly more frequent among tenofo-vir recipients than among patients not receivingtenofovir. 43

Several urine biomarkers have been employed inclinical practice to detect early stages of proximaltubular dysfunction, but most have not been vali-dated in HIV-infected patients. The largest clinical

studies assessing the association of tenofovir treat-ment with kidney toxicity are listed in Table 2 .

RISK FACTORS FOR TENOFOVIR-ASSOCIATEDRENAL TOXICITY

The characterization of demographic, epidemio-logical, and clinical conditions associated with anincreased risk of nephrotoxicity in subjects treatedwith tenofovir is essential to adequately managethese patients.



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Table 2 . Largest clinical studies (including more than 100 patients) evaluating the association of tenofovirtreatment with renal toxicity

Author,year (study)[reference]

Type ofstudy

No. ofpatients

Total or medianfollow-up,weeks

Outcomeassessed

Associationwith TDF

Other risk factorsassociated with renaldysfunction

Gallant JE,2005 (JohnsHopkinsCohort) [44]

R 658 96 GFR (CG) Yes Diabetes, low CD4lymphocyte count

Winston A,2006 [45]

P 948 121 creatinine,anion gap

Yes

Gatanaga H,2006 [40]

CS 160 N.A. Tubulopathy, GFR (CG)

Yes(tubulopathy)

Lopinavir/ritonavir, lowerweight

Fux CA, 2007

(Swiss HIVCohort) [46]

P 1078 86 GFR(MDRD)

Yes Diabetes, PI/r

Young B, 2007(HOPS) [47]

P 1114 44 GFR (CG) Yes

Goicoechea M,2008 [48]

P 146 48 GFR (CG,MDRD)

Yes PI/r

Labarga P, 2009[37]

CS 284 N.A. Tubulopathy Yes Older age

Campbell LJ,2009 [49]

R 3439 104-520 GFR(MDRD),CKD

Yes Indinavir, older age

Calmy A, 2009[39]

CS 153 N.A. Tubulopathy Yes Duration of HIVinfection, PI/r

Overton ET,2009 [50]

CS 845 N.A. GFR(MDRD),CRF

Yes Stavudine, hypertension,hyperlipidemia,proteinuria, lower HIVRNA

Horberg M,2010 (KaiserPermanente)[21]

R 1647 144 GFR(MDRD),tubulopathy

Yes -

Deti EK, 2010(AquitaineCohort) [24]

CS 2588 N.A. GFR (CG) Yes Female gender, olderage, diabetes,hyperlipidemia, lowerCD4 lymphocytecount

Mocroft A, 2010(EuroSIDA)[23]

P 6843 240 GFR (CG) Yes Indinavir, atazanavir,lopinavir/ritonavir

Post FA, 2010(ASSERT) [32]

RC 385 48 GFR(MDRD),tubulopathy

Yes(tubulopathy)

-

Crum-CianoneN, 2010 [51]

CS 717 N.A. GFR(MDRD)

Yes Female gender, blackrace, lower CD4lymphocyte count

(Continued)



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Author,year (study)[reference]

Type ofstudy

No. ofpatients

Total or medianfollow-up,weeks

Outcomeassessed

Associationwith TDF

Other risk factorsassociated with renaldysfunction

Tordato F, 2011(ICONA) [25]

P 1505 144 GFR(MDRD)

Yes Didanosine, PI, femalegender, older age

Calza L, 2011[26]

R 324 96 GFR(MDRD),tubulopathy

Yes PI, older age, diabetes,hypertension

ScherzerR, 2012(Veterans) [28]

R 10,841 202-286 Proteinuria, GFR, CKD

Yes

Squires K, 2003[52]

RC 552 24 creatinine No

Izzedine H,2005 [53]

RC 600 144 GFR (CG) No

Nelson MR,2007 [54]

P 10,343 144 creatinine No Baseline elevatedcreatinine,nephrotoxic drugs,lower weight, olderage, lower CD4lymphocyte count

Arribas JR,2008 (903-934) [55]

RC 517 144 GFR (CG,MDRD)

No

Dejesus E, 2009(AI266073)[31]

RC 300 48 GFR(MDRD) No

Smith KY, 2009(HEAT) [30]

RC 688 96 GFR(MDRD)

No

Gallant JE,2009 (JohnsHopkinsCohort) [29]

P 432 144 GFR(MDRD)

No TDF + PI/r had a greatermedian reductionin GFR than TDF +NNRTI

Martinez E, 2009(BICOMBO)[33]

RC 333 48 GFR (CG) No

ODonnell EP,2011 [56]

R 514 176 GFR(MDRD)

No Older age, lowerweight, hypertension,diabetes, lower CD4lymphocyte count,high HIV RNA

Daar ES, 2011(ACTG 5202)[34]

RC 1857 138 creatinineclearance

No TDF + atazanavir/ ritonavir vs TDF +efavirenz

Note: The studies showing a signicant correlation between tenofovir exposure and renal disease are highlighted by the greybackground. CG = Cockroft-Gault equation; CKD = chronic kidney disease; CRF = chronic renal failure; CS = cross-sectional;GFR = estimated glomerular ltration rate; MDRD = Modication of Diet in Renal Disease equation; NA = not applicable; NNRTI =non-nucleoside reverse transcriptase inhibitor; P = prospective or cohort study; PI = protease inhibitor; PI/r = ritonavir-boostedprotease inhibitor; R = retrospective; RC = randomized, controlled trial; TDF = tenofovir.

Table 2. Continued



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Multivariate analysis of clinical studies andpostmarketing clinical data have identifiedseveral risk factors for developing tenofovir-associated renal toxicity, including older age, black race , low body weight , comorbidit ies(hypertension, diabetes mellitus, chronic hepatitisC), pre-existing nephropathy or renal dysfunction,concomitant use of nephrotoxic drugs or someantiretroviral agents (such as ritonavir-boostedPIs and didanosine), and advanced HIV disease(including low CD4 lymphocyte count, high plasmaHIV viral load, duration of HIV infection, andAIDS).12,17,18,21-26,37-51

These risk factors usually predispose all HIV-infected patients to the development of renaldisease because they could potentiate the renaldamage caused by most nephrotoxic drugs byaltering their pharmacokinetics. In fact, genetic,demographic, and anthropometric variables (race,age, body weight) may inuence hepatic metabo-lism and renal excretion of antiretroviral drugs,leading to an increased plasma exposure to thesecompounds. Comorbidities, underlying renal dis-eases, and concomitant nephrotoxic drugs coulddecrease the renal clearance of tenofovir andincrease the tenofovir concentration in peripheral blood and proximal tubule cells, enhancing the riskof tenofovir toxicity. 17-20

Pharmacokinetic interactions between tenofovirand other coadministered antiretroviral agents areanother risk factor for developing renal dysfunc-tion. Several antiretroviral drugs may interactand synergistically worsen renal function viainduction or inhibition of renal tubule transport-ers. Approximately 70% of the published cases of tenofovir-induced renal toxicity are reported inpatients taking a ritonavir-boosted PI. 14

Ritonavir-boosted PIs may have pharmaco-kinetic interactions with tenofovir, leading to areduced renal clearance of this drug, an increased

plasma concentration, and a more elevated risk of renal toxicity. In fact, tenofovir renal clearance was17.5% slower in subjects taking lopinavir/ritonavircompared with those not taking a PI, after adjust-ing for eGRF differences. 57 Equally, atazanavir/ritonavir and darunavir/ritonavir usually increaseplasma concentrations of tenofovir by approxi-mately 20% to 37%, 58,59 even though data from clini-cal trials show that the long-term coadministrationof tenofovir and boosted PIs is usually safe for thekidney. 34,60,61

An observational cohort study of 445 patientsinitiating a tenofovir-based antiretroviral therapyhas shown that 11% developed a decline in renalfunction (eGFR assessed by CG equation). Inmultivariate analysis, there was a signicant cor-relation between reduced eGFR and concomitantuse of amprenavir and didanosine. 62 The plasmaexposure to didanosine increases by approximately44% to 60% when coadministered with tenofovir,with an increased risk of toxic effects (includingnephrotoxicity) of didanosine. 63 Therefore, thecombination of tenofovir and didanosine should beavoided or reserved for patients with body weight60 kg and normal renal function (a reduction of daily dose of enteric-coated didanosine to 250 mgshould be considered in this case). 14,63

Several cohort studies have shown an increasedrisk of tenofovir-induced nephropathy in patientswith lower CD4 lymphocyte count, longer dura-tion of HIV infection, and AIDS. 24,39,44,51 In a cross-sectional study involving 2,857 HIV-positivepatients receiving HAART, prevalence of protein-uria (spot urine PCR 0.2) was 16% and factorsassociated with presence of proteinuria includedlow CD4 cell count and high plasma HIV viral load(>400 copies/mL). 64

PATHOGENESIS OF TENOFOVIR-ASSOCIATEDRENAL TOXICITY

The nucleotide analogue tenofovir is predomi-nantly eliminated by the kidney via a combinationof glomerular ltration and active tubular secre-tion. The proximal tubule is the main target of tenofovir-induced renal toxicity, because 20% to30% of this drug is excreted unchanged in the urinethrough active secretion by the membrane trans-porters of the tubular cells. Tenofovir inux fromthe blood into the tubular cells is primarily effected by the human-organic anion transporter 1 (hOAT1)

and secondarily effected by hOAT3, localized in the basolateral cell membrane. Afterwards, tenofovirmust be extruded from the tubular cells into thetubular lumen by multidrug resistance protein-4(MRP-4) and by MRP-2, located in the apical cellmembrane. 14,17,18

The proximal tubular cells are especially sus-ceptible to tenofovir toxicity, because they gavea complement of transporters that increase theintracellular concentration of the drug and theyare very rich in mitochondria, which seem to be



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the target organelles of tenofovir cytotoxicity.Tenofovir and other acyclic nucleotides mayinhibit the mitochondrial DNA polymerase anddecrease the amount of mitochondrial DNA, lead-ing to structural and functional mitochondrialabnormalities. Moreover, acyclic nucleotides (suchas adefovir) are known to produce mitochondrialdepletion, inhibition of the respiratory chainenzyme expression, and tubular cell apoptosis bythe release of mitochondrial proteins to the cytosol,including cytochrome C (CytC), which induce thecaspase activation. 17,65

Tenofovir is considered a weaker inhibitor of DNA polymerase than adefovir and cidofovir, andinitial cell culture studies did not show signicantmitochondrial DNA depletion and cellular toxicityin human proximal renal tubules. 66 However, morerecent animal and human studies demonstrate thattenofovir causes decrease in mitochondrial DNAand subsequent mitochondrial toxicity in proximaltubular cells expressing hOAT1. 67,68

The ultrastructural examination of HIV trans-genic mice exposed to tenofovir disclosed severalabnormalities in proximal tubular cells, includ-ing an increased number and irregular shape of mitochondria with sparse fragmented cristae.Laser-capture microdissection showed a decreasedamount of mitochondrial DNA in tubular cells,

while histological analyses of kidney did not showdisruption of glomeruli or proximal tubules. 69 Therole of cell membrane transporters in the tenofovir-induced renal toxicity was also investigated inkidney tissues from transgenic mice. Disruptionof hOAT1 activity was associated with normaltubular amount of mitochondrial DNA, suggest-ing that it prevents inux of tenofovir in tubularcells and subsequent toxicity. On the other hand,disruption of MRP-4 led to an increased numberof irregular mitochondria with fragmented cristae,suggesting that it causes a reduced efux with

subsequent intracellular accumulation of tenofo-vir and toxicity. 70 Electron microscopy studies inpatients with tenofovir-associated tubular toxicityhave also demonstrated widespread morphologicalterations in proximal tubule mitochondria,including reduced mitochondria number, giantand misshapen mitochondria, marked variationsin size and shape, and loss of the normal cristae. 42,71 Tenofovir is an adenosine analogue, but it doesnot induce signicant hepatic depletion in mito-chondrial DNA, in contrast to didanosine (another

adenosine analogue), conrming the importanceof specic cell membrane transporters in increas-ing the intracellular tenofovir amount in proximaltubules. 69

The association of tenofovir with subclinicalmitochondrial damage has been recently con-rmed in a cohort of 101 antiretroviral-experiencedHIV-infected patients who had been switched froma thymidinic backbone to either tenofovir/emtric-itabine or abacavir/lamivudine. After 12 monthsof follow-up, there was no signicant variation ineGFR, median urine protein excretion, microalbu-minuria, or serum phosphate in both groups, whilethere was a signicant increase in urinary excretionof phosphate in patients treated with tenofovir anda signicantly decrease in serum potassium levelsin the abacavir recipients. Moreover, the urinaryexcretion of cytochrome c (which is a marker of mitochondrial toxicity) was signicantly higher intenofovir-treated patients compared to abacavir-treated ones. 72

The coadministered drugs that are substrates forthe same cell membrane transporters may inhibitentrance or exit of tenofovir into or from proximaltubule cells, and increase the plasma or intracellu-lar concentration of the drug and the risk of renaltoxicity. Didanosine is a substrate for hOAT1 andmay impede the inux of tenofovir in tubular cells,

with increased plasma concentration of the drug.Ritonavir is a substrate for MRP-2; it has been sug-gested that it may inhibit the efux from tubularcells into the tubular lumen, with intracellularaccumulation of tenofovir and increased risk of cellular toxicity. 14,17,18

The relationship between tenofovir plasmaconcentration and renal tubular dysfunction has been prospectively examined in 92 HIV-infectedindividuals. Median tenofovir plasma levels weresignicantly higher in subjects with kidney tubu-lar dysfunction than in those with normal tubular

function, suggesting a dose-dependent and plasmaexposure-dependent effect of tenofovir on renaltubular toxicity. 73

It has been recently suggested that geneticpolymorphisms in proximal tubule transport-ers may predispose them to accumulate highintracellular amount of tenofovir and to developtubular dysfunction. ABCC2 and ABCC4 arethe genes that encode the apical membranetransporters MRP-2 and MRP-4, respectively. Ina case-control analysis including 13 tenofovir



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recipients who developed tubular toxicity and17 tenofovir recipients who did not have tubu-lar toxicity, a mutational screening of the genesABCC2 and ABCC4 was performed. A signifi-cant allelic association between the 1249 G Asingle-nucleotide polymorphism (SNP) in theABCC2 gene and tenofovir-induced proximaltubulopathy was observed, and CATC appearedto be a predisposing haplotype for renal toxic-ity. 74 In a cross-sectional study enrolling 115 HIV-infected patients, multivariate analysis showedthat genotype CC at ABCC2 position -24 wasindependently associated with kidney tubulardysfunction. 75 A recent in vitro study has shownthat tenofovir is also a substrate for MRP-10transporter in the apical membrane, and geneticvariability within the ABCC10 gene may influ-ence tubular transport of tenofovir and contrib-ute to the development of tubular dysfunction. 76 These studies suggest that there is a genetic pre-disposition for the development of alterationson tenofovir tubular secretion and subsequenttubular toxicity, but evidence is still insufficientto recommend a routine genetic screening in alltenofovir recipients.

The tenofovir-induced renal toxicity seems to be reversible, but improvement in renal functionafter tenofovir cessation was found to be variable

and incomplete in some studies. A retrospectivestudy involving 24 HIV-infected patients whoceased tenofovir for renal impairment suggeststhat renal toxicity may not always be reversible.After a median follow-up of 13 months followingthe tenofovir cessation, only 10 (42%) patientsreached their pre-tenofovir eGFR (MDRD equa-tion), and greater improvement in eGFR wasassociated with a more rapid decline in eGFR,a shorter duration of tenofovir therapy, and aritonavir-boosted PI therapy associated withtenofovir. 77 Moreover, the renal damage associ-

ated with tenofovir exposure did not appear to be completely reversible in the Veterans HealthAdministration cohort. 28

In other cohort studies, the renal toxicity associ-ated with tenofovir use is largely reversible. Manypatients who develop nephrotoxicity associatedwith tenofovir use have underlying chronic kidneydisease that is usually progressive in nature, andconsequently their eGFR decline may not recoverfully after the drug cessation when the pre-existingnephropathy has progressed over time. 49,78

In conclusion, pathogenesis of kidney tubu-lar toxicity associated with tenofovir treatmentappears to be complex and multifactorial. Increasedplasma exposure and intracellular accumulation inproximal tubule cells play an essential role, alongwith other factors, such as drug-drug interactions,genetic polymorphisms for renal transporter pro-teins, race, age, body weight, and adherence toprescribed therapies.

NEPHROTOXICITY ASSOCIATED WITH NRTIs AND NNRTIs

The use of other NRTIs has been rarely associ-ated with the occurrence of nephrotoxicity in clini-cal trials and cohort studies, but several episodesof glomerular or tubular dysfunction have beenrecognized in subjects treated with these antiretro-viral agents.

Several cases of renal tubular acidosis, Fanconisyndrome, and nephrogenic diabetes insipidushave been described in patients receiving didano-sine, stavudine, lamivudine, or abacavir. 79-81 Otherreports have described some nephrotoxic effectsin association with abacavir treatment, includingacute interstitial nephritis following a hypersen-sitivity reaction 82 and tubular dysfunction withFanconi syndrome and nephrogenic diabetes insip-

idus.83

Moreover, some NRTIs (particularly stavu-dine, didanosine, and zidovudine) may inhibit theDNA polymerase and cause mitochondrial toxic-ity, which can lead very rarely to lactic acidosis andacute renal failure. 84

In particular, a signicant association betweendecline in glomerular function and concurrent useof didanosine has been shown in patients takingtenofovir, as previously reported. 62 In a case report,the antiretroviral regimen containing didanosineand tenofovir has been associated with the occur-rence of Fanconi syndrome and diabetes insipidus

in 3 patients, suggesting that this combinationshould be avoided or frequently monitored fortubular toxicity. 85

Data concerning renal toxicity associated withNNRTI use are very limited, but nevirapine, efa-virenz, and etravirine have usually demonstrateda safe renal prole in controlled clinical trials. Asmall number of cases of crystalluria and uro-lithiasis have been described in subjects takingefavirenz, 86,87 and a single case report linked theuse of efavirenz to a hypersensitivity reaction



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that included interstitial nephritis and acute renalfailure. 88

NEPHROTOXICITY ASSOCIATED WITH PIsAmong PIs, indinavir has been most frequently

associated with renal toxic effects, including intra-tubular drug deposition, crystalluria, nephroli-thiasis, dysuria, hematuria, renal colic, papillarynecrosis, renal atrophy, acute interstitial nephritis,and acute and chronic renal failure. 89,90 Symptomsmay occur as early as 1 week following initiationof indinavir therapy, and urinary crystals com-posed of indinavir can occur in any structure of the kidney and the urinary tract. Crystalluria wasreported in about 20% to 30% of all patients treatedwith this PI, and this condition progressed to neph-rolithiasis in 3% of all subjects. 91

The incidence of urological complications amongindinavir-treated patients in clinical studies wasabout 8 to 10 cases per 100 treatment-years, andrisk factors for the development of nephrolithiasiswere urine pH above 6, low lean body mass level,inadequate hydration, high plasma levels of indi-navir, chronic hepatitis B or C, and concomitanttherapy with low-dose ritonavir or other nephro-toxic drugs. 92-95 Urologic symptoms and elevationsin serum creatinine are usually reversible and nor-

malize within weeks after the discontinuation of indinavir, although irreversible renal damage has been described. 88,89

Several case reports of urolithiasis and acute kid-ney failure were also reported in association withfull-dose ritonavir, saquinavir, nelnavir, fosam-prenavir, and lopinavir-ritonavir therapy, but theincidence of these renal adverse events is extremelylow and their etiology remains still unknown. 96-100

The renal prole of atazanavir was found to be safe in randomized clinical trials and cohortstudies, but several cases of crystalluria, neph-

rolitiasis, and interstitial nephritis were reportedin atazanavir-treated patients. In a retrospectivestudy including 1,134 patients who were receivingritonavir-boosted atazanavir from 2004 through2007, only 11 cases of atazanavir-associated neph-rolithiasis were diagnosed, and all cases occurredwithin 2 years after starting atazanavir treatment.Patients with low water intake, high urinary pH,and a prior history of urinary stones may have agreater risk of urine crystallization. 101 Similarly,30 cases of atazanavir-induced nephrolithiasis

were recorded over a 4-year study period in theAdverse Event Reporting System Database, butno cases of chronic kidney disease were observedin these series. 102 The mechanism of developingrenal stones is unknown, but it is probably linkedto urinary precipitation of atazanavir, as describedfor indinavir stones. Moreover, atazanavir or ata-zanavir/tenofovir therapy has been associatedwith isolated cases of interstitial nephritis andacute renal failure, but withdrawal of antiretrovi-ral treatment resulted in a rapid recovery of renalfunction. 103,104

A more frequent occurrence of nephrotoxic-ity has been reported when atazanavir/ritonaviris administered in association with tenofovir, asemphasized in some previously mentioned clini-cal studies. 23,34 More recently, renal function wasevaluated in a randomized, pilot trial enrolling91 nave patients starting tenofovir/emtricitabineplus atazanavir/ritonavir or efavirenz. The GFRestimated by Chronic Kidney Disease Epidemiol-ogy Collaboration (CKD-EPI) formula 105 basedon creatinine or cystatin C was assessed during a48-week follow-up. Both the CKD-EPI creatinineformula and the cystatin C-based equation showeda signicant decrease in eGFR up to week 48 inpatients receiving atazanavir/ritonavir comparedto a not signicant change of eGFR in those receiv-

ing efavirenz.106

As a whole, the occurrence of glomerular dys-function, urolithiasis, or interstitial nephritis inpatients taking atazanavir appears to be a veryuncommon adverse event, given that atazanavirhas been administered to a very high number of patients worldwide.

OTHER ANTIRETROVIRAL AGENTS ANDNEPHROTOXICITY

Data from clinical trials have shown that fusion

inhibitors (enfuvirtide), CCR5-receptor antagonists(maraviroc), and integrase inhibitors (raltegravir)do not have signicant nephrotoxic effects, andtheir clinical use is usually associated with a saferenal prole. 107-110

In the safety analysis of TORO-1 and TORO-2trials including over 600 patients receiving enfu-virtide, only one patient with previous history of proteinuria and hematuria exhibited a hypersensi-tivity reaction complicated by a membranoprolif-erative nephritis. 107



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However, available data are still limited. Further,enlarged studies are requested to better investigatepotential renal adverse events of new antiretroviralagents.

SCREENING, DIAGNOSIS, AND MANAGEMENT

The most appropriate management of potentialrenal toxicity associated with antiretroviral therapyshould focus on detection of risk factors for renaldisease, diagnosis of preexisting renal impairment,screening for early glomerular or tubular dysfunc-tion, avoidance of drugs that can produce renaltoxicity or inhibit renal elimination, and adjust-ment of antiretroviral doses or discontinuation of antiretroviral drugs in accordance with the level of renal impairment.

Before starting antiretroviral therapy, all patientswith HIV infection should be screened for renaldisease. This baseline evaluation should includerisk factors, comorbidites, and basic parametersof glomerular and tubular function. Risk factorsfor renal disease include African American race,age >50 years, family history of renal disease, con-comitant use of nephrotoxic drugs, diagnosis of AIDS, CD4 lymphocyte count 4000 copies/mL. Comorbiditiesinclude diabetes mellitus, arterial hypertension,

chronic hepatitis C, and pre-existing chronic kid-ney disease (CKD). Metabolic abnormalities (suchas hyperlipidaemia and insulin resistance) should be investigated because they can lead to vascularnephropathy. 10-14 CKD is dened as either kidneydamage or GFR


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estimate for clinical use in HIV-infected personsremains unclear. 10-14,35 Depending on the methodused (CG or MDRD), signicant differences areobserved in the percentage of patients who havedecreased eGFR and who require a reduction inthe antiretroviral dosage. 116 Moreover, a persistentdecline in estimated GFR (by CG formula) but notin measured GFR (by iothalamate clearance) intenofovir recipients may reect tubular rather thanglomerular toxicity, because the drug may inhibittubular creatinine excretion and lead to increasedcreatinine serum level. 117,118

Because most studies investigating pharma-cokinetic changes in subjects with renal failurehave employed the CG formula, this equation isrecommended by the Infectious Disease Society of America for medication dose adjustments in HIV-positive patients. 10 More recently, the EuropeanAIDS Clinical Society Guidelines have recom-mended the MDRD formula for the baseline andperiodic evaluation of GFR in HIV-infected per-sons. 16 The detection of eGFR 300 mg or with PCR >0.3mg/mg. 10-14,118

The suggested algorithm for screening renaldisease and monitoring renal function in patientsreceiving antiretroviral therapy is summarized inFigure 1 .

In case of a decline in eGFR below60 mL/min/1.73 m 2 (by MDRD formula), thedosages of antiretroviral agents should be reduced,if necessary ( Table 3 ). In subjects using antiretro-viral agents with associated risk of nephrolithiasisor interstitial nephritis (atazanavir, indinavir),eGFR and urinalysis (for crystalluria) should beregularly performed. In case of crystalluria, hae-maturia, leucocyturia, eosinophiluria, loin pain, orprogressive decline in eGFR, renal tract imaging(ultrasound or CT scan) and nephrologic consult-ing are recommended. Discontinuation of currentdrugs should be considered when diagnosis of nephrolithiasis or nephritis has been made andother causes of these nephropathies have been

excluded.10,16

A careful monitoring for kidney toxicity should be performed in patients using tenofovir, and theproposed algorithm is depicted in Figure 2 .

A basic evaluation including eGFR, urinaly-sis, and serum phosphorus should be per-formed before the start of tenofovir-basedtreatment; it should be repeated every 3 months,if patients meet at least one of the criteria for anincreased risk of kidney toxicity (see Figure 2 ).In case of confirmed hypophosphoremia (serumphosphorus


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Figure 1. Suggested algorithm for screening and monitoring renal abnormalities in HIV-infected patients whostart antiretroviral therapy. HCV = hepatitis C virus; AIDS = acquired immunodeciency syndrome; eGFR =estimated glomerular ltration rate; CG = Cockroft-Gault formula; MDRD = Modication of Diet in Renal Diseasesformula; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration formula; PCR = protein-to-creatinineratio.

1-Evaluation of risk factors for renal disease:

2- Screening study:

African-American race, age >50 years, family history of renal disease, diabetes, hypertension, HCVcoinfection, use of nephrotoxic drugs, AIDS, CD4 lymphocyte count 4000 copies/mL

serum creatinine and eGFR (CG or MDRD or CKD-EPI) Spot urine analysis (for proteinuria)

eGFR < 60 mL/min/1.73 m 2

Stop nephrotoxic drugs Reduce dosage of

antiretroviral drugs Perform renal ultrasound

Assess proteinuria in 24-hourcollected urine or spot urine PCR

Perform renal ultrasound

24-hour proteinuria >300 mgorspot urine PCR >0,3 mg/mgorabnormal renal ultrasound

24-hour proteinuria 300 mgandspot urine PCR 0,3 mg/mgandnormal renal ultrasound

Referral to a nephrologist(eventual renal biopsy)

Repeat periodically screening testsbased on clinical and laboratory

abnormalities and at least once-a-year inpresence of 1 risk factors for renal

disease(return to point 2)

Protenuria +1 or 30 mg/dL eGFR 60 mL/min/1.73 m 2andprotenuria absent or


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Table 3 . Summary of dose reductions recommended for antiretroviral drugs in patients with renalimpairment 15,16,118

Class Drug Recommended daily dosing in patients with renalimpairment

NRTIs Abacavir No adaptation necessaryNo data for end-stage renal disease

Didanosine Dosage (once daily)Body weight


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Class Drug Recommended daily dosing in patients with renalimpairment

Nelnavir, indinavir,fosamprenavir, saquinavir,darunavir, tipranavir

No adaptation necessary

Lopinavir No adaptation necessary Avoid once-daily dosage in patients on HD

Entry inhibitors Enfuvirtide No adaptation necessary

Maraviroc CrCl


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Evaluation of eGFR (CG or MDRD or CKD-EPI), serumphosphorus and urinalysis before the start of TDF therapy

Serum phosphorus 30 mg/dL

eGFR


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