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REVIEW NEPHROLOGY

Renal Concerns in the Treatment of Chronic Hepatitis B with Tenofovir

Giuseppe Coppolino
1
, Valeria Cernaro

2
, Laura Rivoli

3
, Angela Pinciaroli

1
, Davide Bolignano

4

1Nephrology and Dialysis Unit, “Pugliese-Ciaccio” Hospital of Catanzaro, Catanzaro, Italy; 2Department of Clinical and Experimental Medicine,
University of Messina, Messina, Italy; 3Unit of Nephrology and Dialysis, University-Hospital “Magna Graecia” of Catanzaro, Catanzaro, Italy;
4CNR – Institute of Clinical Physiology, Reggio Calabria, Italy

Abstract

Tenofovir, a third generation oral nucleos(t)ide analogue, currently represents one of the first-line drugs recommended for treating
chronic hepatitis B virus (HBV) infection. After oral administration, tenofovir is mostly excreted in the urine by glomerular
filtration and proximal tubular secretion. Hence, an impaired kidney function may lead to an increased renal exposure to the
drug in patients with coexistent renal damage. This could further worsen kidney disease through different mechanisms of
nephrotoxicity such as mitochondrial DNA depletion and tubular cytotoxicity. Despite several studies performed so far to assess
tenofovir-related renal toxicity, data in HBV patients are not yet conclusive. Screening of risk factors for kidney disease before
starting therapy and a careful monitoring of serum creatinine, glomerular filtration rate, serum phosphate and urine analysis
during treatment are advocated to adjust the dose or stop treatment if needed. New biomarkers of tubular injury, such as neu-
trophil gelatinase associated lipocalin, could become helpful in the future for the timely identification and risk stratification of
renal damage induced by tenofovir.

Keywords: antiretroviral therapy; hepatitis B; NGAL; nucleos(t)ide analogue; tenofovir

Received: 10 February 2017; Accepted after revision: 03 March 2017; Published: 23 March 2017.

Author for correspondence: Davide Bolignano, CNR – Institute of Clinical Physiology, c/o EUROLINE, Via Vallone Petrara 55–57, 89124
Reggio Calabria, Italy. Email: davide.bolignano@gmail.com

How to cite: Coppolino G et al. Renal Concerns in the Treatment of Chronic Hepatitis B with Tenofovir. J Ren Hepat Disord 2017;1(1):50–54.

DOI: http://dx.doi.org/10.15586/jrenhep.2017.11

Copyright: Coppolino G et al.

License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/
licenses/by/4.0

Introduction

Chronic hepatitis B virus (HBV) infection is a relevant public
health problem all over the world, with different prevalence
between low-income and high-income countries. The virus
responsible for the disease is a hepatotropic virus belonging
to the Hepadnaviridae family (1). Vaccination is recommended
by the World Health Organization in all newborns and in unvac-
cinated subjects, particularly in high-risk individuals including
haemodialysis patients, recipients of organ transplantation or
blood transfusion, partners of patients with HBV infection and
people who travel to endemic areas (2). Nevertheless, HBV

infection is still widespread. Because patients affected are at
high risk of morbidity and mortality, primarily related to the
development and progression of liver cirrhosis and cancer, iden-
tifying the most effective therapeutic options is mandatory (3).
The drugs currently recommended as first-line therapy of
chronic HBV infection are interferon (IFN) or third-generation
oral nucleos(t)ide analogues, such as tenofovir and entecavir
(ETV). According to current guidelines, the use of lamivudine
(LAM), telbivudine and adefovir (ADV) as first-line drugs is
not recommended because of their limited efficacy, their side

Journal of Renal and Hepatic Disorders 2017; 1(1): 50–54

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http://dx.doi.org/10.15586/jrenhep.2017.11
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effects and the higher rates of drug resistance. IFN is indicated in
young patients with mild-to-moderate liver disease, but it cannot
be prescribed in patients with non-compensated liver disorder,
autoimmune disease, psychosis, depression and during preg-
nancy. Also, IFN should not be prescribed in renal transplant
recipients because of the increased risk of rejection, although
this drug has the advantage of limited treatment duration with
the hypothetic absence of drug resistance. Long-term treatment
with nucleos(t)ide analogues is necessary for patients not achiev-
ing sustained virological response or for those needing extended
therapy (4).

Tenofovir: pharmacokinetics and mechanisms of

action

Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse
transcriptase inhibitor acting as a structural analogue of
the usual substrate for viral RNA–directed DNA polymerase
used against the human immunodeficiency (HIV) and hepati-
tis B (HBV) viruses. Tenofovir has been used worldwide
since 2001 as part of a highly active antiretroviral therapy
(HAART) against HIV infection. Since 2008, it has been indi-
cated for the treatment of adults with chronic HBV infection
or HIV/HBV co-infection. It is administered orally as the pro-
drug TDF or tenofovir alafenamide (5, 6). Following oral
administration, TDF is essentially completely absorbed in
the gastrointestinal tract and peak plasma concentrations
are reached within 0.25–1.5 h. The prodrug moiety of TDF
is efficiently cleaved and minimal intact prodrug is observed
in systemic circulation. Major sites of tissue uptake include
the liver, kidney and bowel. Half-life of TDF is approxi-
mately 17 h. The kidney eliminates TDF with minimal
metabolic transformation. After an oral dose, 70%–80% is
excreted in the urine unchanged. Although side effects are
mostly represented by bone mineral diseases, gastrointestinal
disorders and acute pancreatitis, concerns have been raised
also about potential renal damage. In fact, specific renal
metabolism leads TDF to be eliminated through urine by glo-
merular filtration (80%) and proximal tubular secretion (20%)
(7). Renal clearance abnormalities may affect TDF pharma-
cokinetics and systemic concentration, and the consequent
increased renal exposure to this drug in patients with different
degrees of coexistent kidney damage could result in a further
decline of renal function (8).

Mechanisms of tenofovir-induced renal toxicity

TDF nephrotoxicity may be explained by various mechanisms
including mitochondrial DNA depletion, tubular cytotoxicity
and intra-individual differences in TDF clearance because of
polymorphisms in genes encoding for drug transporters (9, 10).
TDF acts primarily by disturbing the mitochondrial function
through the inhibition of DNA polymerase-gamma responsible
forDNAreplicationandbydepletingdifferentenzymesinvolved
in the electron transport chain function and oxidative

phosphorylation. In vitro experimental studies demonstrated
the potential of TDF to induce mitochondrial dysfunction but
with a lower toxicity as compared to other nucleoside reverse
transcriptase inhibitors (10). After absorption, TDF is phos-
phorylated in two sites and it is filtered unmodified through the
glomerulus, beingforlittleparttakenfromthebloodbytheprox-
imal tubular cells (11). As a consequence of phosphorylation, the
drug is activated and becomes a structural analogue of the usual
substrateofviralRNA–directedDNApolymerase.Thedrughas
theabilitytohaltviralDNAsynthesisbyinhibitingtheactivityof
host alfa- and beta-DNA polymerases and mitochondrial DNA
gamma-polymerase. This mechanism is useful to stop viral repli-
cation but is also at the basis of TDF-induced mitochondriopa-
thies, in particular, in the kidney proximal tubule. In the
basolateral membrane of the proximal tubular epithelial cells,
provided with numerous mitochondria, TDF is implicated in
active cellular uptake by the organic anion transporters
hOAT1 and hOAT3. In the apical membrane, TDF takes part
in the process of active uptake mediated by multidrug resistance
proteins MRP-2 and MRP-4 (12). hOAT-1 and hOAT-3 are
responsible for carrying 20%–30% drug into the proximal tubule
cells for its elimination by urine. Secretion into the urinary space
is mediated also by MRP-2 and MRP-4 on the apical membrane
(13). TDF affinity for hOAT-1 and hOAT-3 is at the basis of
TDF nephrotoxicity. Moreover, interaction with MRP-2 and
MRP-4 may induce mitochondrial DNA depletion and dysfunc-
tion, with renal accumulation of the drug (14, 15). TDF may
cause different kinds of renal damage, including proximal tubu-
lar dysfunction such as Fanconi syndrome, hyperphosphaturia
and normal phosphataemia in patients with preserved or
decreased renal function, acute interstitial nephritis, acute tubu-
lar necrosis and acute kidney injury. Renal biopsies in patients
treated with TDF usually show normal glomeruli and necrotic
or apoptotic tubular epithelial cells (12, 16). Rats treated with
300 mg/kg of TDF for 28 days showed increased tubular hyaline
droplets positive for α2-microglobulin; electron microscopy
revealed condensed, fibrillar electron-dense material in the prox-
imal convoluted tubule epithelial cells (17).

Tenofovir and renal function in clinical trials

Renal toxicity due to TDF is clearly described in the literature
(11, 18, 19), but many studies were designed to demonstrate
the long-term safety and efficacy of TDF in chronic HBV
patients with normal or impaired renal function (20). A
decline of estimated glomerular filtration rate (eGFR) was
observed in patients with mild-to-moderate renal disease
before therapy and in patients with normal renal function
(13–15). In HIV-infected patients, TDF leads to a significant
decline in creatinine clearance (CrCL) compared with non-
TDF-containing regimens which is reversible partially or
completely after drug discontinuation (8, 21). Clinical trials
seem to suggest that TDF does not interfere with renal safety
in HBV population and dose adjustment according to basal
GFR does not influence viral response to therapy, preventing

Renal concerns with tenofovir therapy

Journal of Renal and Hepatic Disorders 2017; 1(1): 50–54 51



renal side effects (22). A similar safety profile has been
described in subjects with normal GFR and in those with
mild renal impairment at baseline. Fixed thresholds for renal
TDF toxicity included an increase of 0.5 mg/dl serum creatinine
(sCr) from baseline (23). In a randomised clinical trial (24),
patients did not experience renal failure or progressive dete-
rioration in renal function, although the majority (80%) had
mild renal impairment. Furthermore, sCr levels remained
stable within each CrCL category over the course of the
study and the mean CrCL values remained relatively stable
over time. In spite of these findings, the severity and the risk
of TDF-associated nephrotoxicity in patients with chronic
hepatitis B without pre-existing renal disease or facilitating fac-
tors for renal involvement are still not well defined (25–27).
Moreover, a Cockroft–Gault estimated CrCL ≥70 ml/min is
an entry criterion for most clinical trials now available, limiting
the experience in patients with established renal damage (23). In
preliminary data of naïve patients treated with TDF or ETV,
the risk of renal function worsening was similar in both groups;
older age and impaired renal function before starting therapy
were predictors of renal damage during treatment (28).

Combined antiviral therapy (TDF plus ETV) was not asso-
ciated with increased risk of renal damage when compared
with ETV monotherapy. In a recent study, the increase of sCr
values (≥0.3 mg/dl) had similar frequency in patients receiving
combined therapy or monotherapy at week 96. Elevation of
sCr levels above 0.5 mg/dl was more frequent in patients in
monotherapy, but in any case, antiviral drug dose reduction
was necessary (29). Renal safety profile of the new prodrug teno-
fovir alafenamide fumarate (TAF) seemed to be different from
TDF. TAF showed no in vitro interaction with hOAT receptors,
whichareinvolvedinrenalTDFnephrotoxicity(30,31).Aphase
2studywasperformedinHIVpatientstocomparethesafetypro-
file of TAF with that of TDF. Patients treated with TAF had
a similar virological response, a smaller reduction of CrCL
and lower proteinuria than patients treated with TDF after
48 weeks of therapy. TAF effective dosage was lower than
TDF (10 mg vs. 300 mg) (32).

Tenofovir in kidney transplantation and haemo-

dialysis patients

TDF is even less studied and used in kidney transplant recipients,
probably because of its potential nephrotoxic effect. After liver
transplantation, additional nephrotoxicity should also be consid-
ered because of the concomitant use of calcineurin inhibitors
(24). Recently, a study was performed using TDF in solid
organ recipients, including three kidney transplant recipients.
Patients were partial responders to previous therapies with
other nucleos(t)ide agents. Renal parameters were stable after
12 months of therapy, and nearly half of the patients were
HBV DNA negative at month 12 (33).

In a retrospective community-based cohort study by Gish
et al. (23), sCr increased by 0.2 mg/dl from basal levels in

18.8% non-transplant patients receiving TDF; a similar inci-
dence (20.9%) of sCr increase was reported in patients treated
withETV.Inthisstudy,transplantationandpre-existingreduced
renal function were the only factors independently associated
with sCr increase. Long-term studies performed with LAM
showed reduced mortality rates and improved patient survival
in kidney transplant recipients with HBV infection. Also, in
patients undergoing haemodialysis, long-term use of TDF has
been poorly studied. Sparse evidenceindicatesthat high-fluxhae-
modialysis is able to remove TDF efficaciously. According to
this finding, it is now being recommended to treat HBV patients
on haemodialysis with 300 mg TDF once a week after the
12th hour of dialysis (34).

Dose adjustment of TDF and early diagnosis of

TDF-related renal damage

The American Association for the Study of Liver Diseases
(AASLD) guidelines recommend to measure eGFR, phospha-
turia, urine protein/creatinine ratio, glycosuria and tubular
proteinuria in patients with HIV infection every 6 months
during TDF therapy. They recommend to reduce TDF dosage
if eGFR is below 60 ml/min and to stop TDF treatment
if eGFR, phosphaturia, urine protein/creatinine ratio and gly-
cosuria change significantly (35). In patients with chronic
HBV infection, sCr, eGFR (with Cockcroft–Gault formula)
and phosphataemia should be measured before and every
6 months during TDF exposure. Particular attention has to
be given in patients at higher risk for kidney disease and in hae-
modialysis patients. In patients at risk for renal disease, renal
parameters must be measured every month during the first
3 months of therapy, then every 3 months until the end of
the first year and every 6 months thereafter. Patients develop-
ing eGFR <60 ml/min and/or serum phosphorus <2 mg/dl
during therapy have to be monitored more closely. TDF
dosage adjustment is required in patients with GFR <50 ml/
min (2). Lampertico et al. suggested making dose reduction
also in patients with eGFR <60 ml/min [estimated using Mod-
ification of Diet in Renal Disease (MDRD) study equation]
and/or low levels of serum phosphorus. In their study cohort,
the estimated cumulative probability of dose reduction for
renal adverse events was 11% for naïve patients and 24% in
patients previously treated with ADV at month 48 (36, 37).
Many studies were performed to compare the available equa-

tions to calculate eGFR in HBV patients. Indeed, establishing
what is the better formula is already a challenging question
for practical nephrology. In the general population, the
MDRD study equation is usually more accurate than the Cock-
roft–Gault equation; however, in some cases, both formulas
showed similar results. In particular, the Cockroft–Gault equa-
tion is less accurate than the MDRD equation in older and
obese patients, whereas the MDRD study equation should
not be applied to children, during pregnancy, to patients aged
>85 years or those belonging to some racial or ethnic subgroups,

Coppolino G et al.

Journal of Renal and Hepatic Disorders 2017; 1(1): 50–54 52



such as Hispanic people. MDRD formula is also less accurate in
patients affected by diabetes mellitus type 1 without micro albu-
minuria and in kidney transplants donors (because its accuracy
decreases for eGFR >60 ml/min). The Kidney Disease Improv-
ing Global Outcomes (KDIGO) 2013 guidelines recommend to
use the new Chronic Kidney Disease Epidemiology Collabora-
tion (CKD-EPI) formula, which is more accurate than MDRD
for eGFR values >60 ml/min and generally improves perfor-
mances of MDRD equation. Yet, the Cockroft–Gault equation
is still largely used for drug adjustment recommendations,
because kidney function was estimated by this formula in the
majority of pharmacokinetics studies (38, 39). New markers
of tubular dysfunction, such as neutrophil gelatinase-associated
lipocalin (NGAL), may be used to evaluate kidney damage dur-
ing TDF therapy (40–42). In the past, various studies have been
published demonstrating the usefulness of NGAL as an early
biomarker of tubular damage in HIV-infected patients treated
with TDF (43–46). Conversely, the body of evidence in HBV
patients, at present, is equivocal. In a randomised clinical trial,
HIV patients treated with TDF showed an increase in NGAL
values when compared with those treated with abacavir
(44); however, more recent studies did not show significant dif-
ferences in plasma and urinary NGAL after TDF treatment
(45, 46).

Conclusion

Despite a large body of evidence has accrued on the safety
profile of TDF therapy in HIV-infected patients, clinical gui-
dance in the chronic hepatitis B population requires further
insights, in particular, with respect to renal toxicity and
bone mineral disease incidence. Screening of risk factors for
renal disease before starting TDF therapy and a careful mon-
itoring of sCr, eGFR, serum phosphate and urine analysis
during treatment are important mainstays for guiding the pre-
scription of this drug and to promptly reduce dosage or inter-
rupt therapy if nephrotoxicity occurs. Monitoring early renal
damage by implementing new biomarkers such as NGAL
could improve timely diagnosis of tubular dysfunction due
to TDF. New evidence on TAF, the new oral prodrug of
tenofovir, in the HBV population is strongly advocated as
this agent has already shown promising results with respect
to renal and bone safety in the HIV population.

Conflict of interest

The authors declare no conflict of interest.

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