Elias, Adikwu, Et Al. 2014

Pharmacology & Pharmacy, 2014, 5, 97-111
Published Online January 2014 (http://www.scirp.org/journal/pp)

http://dx.doi.org/10.4236/pp.2014.51015
Tenofovir Renal Toxicity: Evaluation of Cohorts and

Clinical Studies—Part 2
Adikwu Elias1*, Ogbuehi Ijeoma1, Nkereuwen Jonathan Edikpo1, Deo Oputiri2,
Oru-Bo Precious Geoffrey2
1
Department of Pharmacology, Faculty of Basic Medical Sciences, University of Port Harcourt, Choba, Rivers State, Nigeria; 2De-
partment of Pharm Tech, College of Health Sciences, Otuogidi, Bayelsa State, Nigeria.
Email: *[email protected]
Received December 2nd, 2013; revised December 29th, 2013; accepted January 12th, 2014
Copyright © 2014 Adikwu Elias et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In accor-
dance of the Creative Commons Attribution License all Copyrights © 2014 are reserved for SCIRP and the owner of the intellectual
property Adikwu Elias et al. All Copyright © 2014 are guarded by law and by SCIRP as a guardian.
ABSTRACT
Tenofovir is a nucleotide reverse transcriptase inhibitor used as part of antiretroviral regimens. It is well tole-
rated with relative toxicological effects but recent reports have linked it with renal toxicity which is of clinical
concern. This study reviews literary work on tenofovir renal toxicity with more light on case reports. Tenofovir
renal toxicity manifests as Fanconi’s syndrome, nephrogenic diabetes insipidus and acute renal failure. Fanco-
ni’s syndrome is characterised by acidosis, protenuria, albuminuria, aminoaciduria, hyperchloremic, metabolic
acidosis, hypouricemia, hypophosphatemia and glycosuria. The presence of urine osmolality, polydipsia and po-
lyuria could give credence totenofovir induced nephrogenic diabetes insipidus. In some cases of tenofovir renal
toxicity, renal biopsy revealed sclerosed glomeruli with ischemic injury including portal collapse of capillary
loops. Histopathological changes in glumeruli include mild mesangial proliferation, increased mesangial matrix
and thickened capillary loops. Moderate degenerative tubular changes, loss of tubular mass, interstitial scarring
and scattered cellular infiltrates. Pharmacodynamic and pharmacokinetic interactions may occur with the co
administration of tenofovir with non steroidal anti-inflammatory drugs, aminoglycosides and some protease in-
hibitors which may potentiate renal toxicity. Tenofovir renal toxicity is associated with some risk factors includ-
ing genetic polymorphism as supported by dichotomy in renal toxicity among different race and the association
between ABCC2 gene and tenofovir kidney tubular dysfunction. The pharmacology of tenofovir renal toxicity is
unclear but it is attributed to the interaction between tenofovir and theorganic anion transporters (hOAT1, and
to a lesser extent, OAT3) favoring intracellular accumulation in renal proximal tubule cells. This may lead to
ultrastructural mitochondrial abnormalities and decreased mtDNA levels which could stimulate reactive oxygen
species production, depletion of antioxidants and antioxidant enzymes. These processes can stimulate the destruc-
tion of biomolecules such as DNA, proteins, and lipids, thus causing the deregulation of redox-sensitive metabolic
pathways, signaling pathways, and cell death. Despite tenofovir renal toxicity it has achieved notable therapeutic
success nevertheless patients on tenofovir containing regimens should be monitored for renal function parameters.
Co administration with potential nephrotoxic drugs should be avoided except when benefit outweighs risk.
KEYWORDS
Tenofovir; Renal; Toxicity; Interactions; Polymorphism; Pharmacology
1. Introduction neous cells. It is the major organ of excretion and ho-

meostasis for water-soluble molecules; it can concentrate
The nephron is the functional unit of the kidney and con-
certain substances actively. Its cells can bioconvert
sists of a continuous tube of highly specialized heteroge-
chemicals and metabolically activate a variety of chemi-
*
Corresponding author. cal substances [1]. To limit both systemic exposure and
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98 Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies—Part 2
the duration of the pharmacological or toxicological ef- part of this work we reviewed HIV associated renal
fects, of these substances they are rapidly and efficiently nephropathy, HIVAN was observed to be prominent in
eliminated via the kidney as part of the fundamental de- HIV positive patients of African origin. This observation
fense system of our body. Some drug substances are ac- was reported to have genetic predisposition, and inci-
tively transported across the renal proximal tubule by dence is equally associated with higher viral load. Re-
drug transporters followed by elimination via the urine searchers were able to classify HIV associated renal ne-
which is a major pathway in the detoxification process phropathy probably due to the evaluation of different and
[2]. Some of these eliminated drugs are toxic and their unique characteristic manifestations. Commonly known
contact with drug transporters in tubular cells is the first classifications include HIV associated nephropathy
fundamental stage in the development of their nephro- (HIVAN), immune complex-mediated glomerulonephri-
toxic process. Most drug substances become nephrotoxic tis, andthrombotic microangiopathies (TMA).
only after transportation into the proximal tubular cells.
Recent advances have identified families of drug trans- 2.1. HIV Associated Nephropathy
porters which are expressed in the proximal tubule [3].
It is a disease caused by focal glomerulosclerosis with
Of the identified transporters, the organic anion trans-
severe proteinuria, renal failure, and rapid progression to
porters (hOAT1, and to a lesser extent, OAT3) in the
ESRD. It has become the most common cause of end
basolateral membrane are responsible for the active trans-
stage renal disease in HIV patients. Studies have shown
portation of tenofovir into renal proximal tubule cells
that HIVAN is more prevalent in patients of African
[4,5], subsequently the drug is secreted to the tubular
descent [13,14]. The estimated prevalence of HIVAN has
lumen by the apical membrane transporters (multidrug
ranged from 3.5% in clinical studies to 12% in autopsy
resistance proteins, 4 and 2) [6]. Tenofovir may interact
studies [15]. Renal biopsy is one of the most fundamental
with these transporters leading to excessive entry or re-
means to establish the diagnosis of HIVAN. Characteris-
duced outflow of tenovoir favoring intracellular accumu-
tic histopathological findings include collapsing focal
lation and increasing renal toxicity. Proximal tubular cell
and segmental glomerulosclerosis, tubular epithelial atro-
secretion of tenofovir explains the accumulation of the
phy with microcystic dilatation of the tubules and lym-
drug in these mitochondria-rich cells leading to mito-
phocytic interstitial infiltration [16]. Viral infection of
chondrial damage. Despite initial evaluations which gave
renal cells seems to play an important role in the patho-
credence to the renal safety of tenofovir, reports have
genesis of HIVAN. In 2002 Marras and others reported
associated tenofovir with significant risk of renal toxicity
that renaltubular cells in patients with HIVN could serve
in human and animal studies. Tenofovir nephrotoxicity is
as a reservoir which facilitates active replication of
characterized by proximal tubular cell dysfunction that
HIV-1 independent of various peripheral blood mono-
may be associated with acute kidney injury or chronic
nuclear cells [17].
kidney injury [7]. Several case reports describing renal
toxicity attributable to tenofovir have been published,
2.2. Immune Complex-Mediated
with manifestations of Fanconi syndrome, nephrogenic
Glomerulonephritis
diabetes insipidus and acute renal failure being reported
[8,9]. Fanconi’s syndrome is characterised by acidosis, A multitude of immune complex-mediated glomerulo-
protenuria, aminoaciduria, hypophosphatamia and gly- nephritis have been reported as causes of chronic kidney
cosuria [10]. In some cases histopathological changes in disease in HIV infected patients. The prevalence of HIV
renal toxicity revealed proximal tubular injury and vary- associated, immune complex-mediated glomerulonephri-
ing degrees of chronic tubulointerstitial scarring. Promi- tis has been estimated to be 15% - 80% in various au-
nent eosinophilic inclusions within proximal tubular cell topsy and biopsy study in HIV infected patients. Ac-
cytoplasm and alteration in mitochondria structure and cording to some authors Immune complex-mediated glo-
function were also observed [11,12]. Due to tenofovir re- merulonephritis may present as postinfectious glomeru-
ported renal toxicity, in our initial study—Part one, we lonephritis, membranous nephritis, IgA nephritis, fibril-
critically looked at cohorts and clinical studies. In this lary glomerulonephritis, immunotactoid glomerulopathy,
second part, we are evaluated case reports, genetic factors, and membranoproliferative glomerulonephritis [18]. In
pharmacology of tenofovir renal toxicity and the implica- general, HIVAN is mainly limited to patients of African
tions of drug-drug interactions on tenofovir renal toxicity. descent, whereas most cases of renal disease in the white
population seem to be immune complex-mediated glo-
2. Types of Renal Toxicity in HIV merulonephritis [19].
In spite the fact that some antiretroviral drugs are asso-
2.3. Thrombotic Microangiopathies (TMA)
ciated with renal toxicity, HIV is also associated with
some forms of renal damage (nephropathy). In the first Thrombotic microangiopathies involving kidney was first
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Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies—Part 2 99
described in AIDS patient by Boccia et al. in 1984, but tremendous improvement in renal function of HIV pa-
subsequently, several hundred cases have been reported tients with renal impairment observed after initiation of
worldwide [20]. TMA occurs with an annual incidence of HAART. In one of the cohorts HIV positive renal im-
3.7 cases per 100 000 persons in the general population paired patients improved with HAART treatment with
and is lightly more common in females (female:male respect to non HAART treated patients [33]. Also Pre-
ratio 3:2) [21-23]. TMA is a heterogeneous group of dis- liminary data from 3313 patients who were enrolled in a
orders characterized by histopathological lesion of vessel randomized antiretroviral trial in Uganda and Zimbabwe
wall thickening (mainly arterioles or capillaries), intra- demonstrated stabilization or slight improvement in kid-
luminal platelet thrombosis and obstruction of the vessel ney function after the initiation of HAART [34]. In a
lumina. Consumption of platelets and erythrocytes occurs comparative cohort of patients with HIV biopsy proven
in the microvasculature of kidney, brain and other organs, HIVAN in the pre-HAART and in the HAART era re-
which causes laboratory features of thrombocytopenia ports revealed improvement in HIV associated renal
and microangiopathic hemolytic anemia [24]. Haemolyt- function during the HAART era [35]. A cohort of 263
ic uraemic syndrome (HUS) and thrombotic thrombocy- consecutive HIV-infected patients referred to the Johns
topenic purpura (TTP) are classical forms of thrombotic Hopkins renal clinic from 1995 to 2004 was examined.
microangiopathy (TMA) which are characterize by mi- Patients were included if they had biopsy-proven HIVAN
croangiopathic haemolytic anaemia with renal insuffi- and did not require dialysis within 1 month of their kid-
ciency along with other features such as thrombocytope- ney biopsy. Fifty-three patients among 152 biopsied pa-
nia, fever, and neurological changes [25,26]. It can also tients had HIVAN. Among 36 patients who met the in-
be observed in association with pregnancy, cancer, che- clusion criteria, 26 were treated with ART (group I) and
motherapy, human immunodeficiency (HIV) infection 10 patients were not (group II). It was observed that Pa-
and malignant hypertension [27]. tients with biopsy-proven HIVAN treated with ART had
better renal survival compared with patients who did not
3. Role of Antiretroviral in HIV Associated receive ART [36].
Renal Disease The beneficial effects of HAART on HIV associated
renal disease have been shown in individual clinical ob-
Despite HIV associate renal disease the advent of highly
servations. There are reports of resolution of renal dis-
active antiretroviral therapy in the management of HIV
ease with the administration of HAART, with a recur-
hasdecreases the incidence of HIV associated renal dis-
rence of renal disease after stopping treatment [37]. It is
ease. One of the primary impacts that is vividly visible is
recognized that HAART prevents or reduces the risk of
the decrease in HIV associated mortality and morbidity
developing HIVAN and if this occurs, HAART treated
rates. A clearer picture of conspicuous impact could be
patients may have a slower course and lower mortality
ascertained from the outstanding literary work of Wyatt
than in untreated patients [38]. Successful transplanta-
and Klotman [28] who reported that the widespread in-
tions in HIV-infected patients who have received highly
troduction of HAART in 1996, led to a drastic decline in
active antiretroviral therapy and have undetectable viral
AIDS-related deaths in the United States. They further
loads have been reported. One of these reports can be
stated that the proportion of deaths that are attributable to
seen from the work of Murphy and colleagues who
AIDS-defining conditions has continued to decline, with
transplanted kidneys in 23 patients who were receiving
chronic complications such as liver and kidney disease
antiretroviral therapy and observed a graft survival rate
becoming increasingly important contributors to mortal-
of 87%. Case reports have also shown the impact of an-
ity in the HAART era. At the same time, there has been a
tiretroviral drugs on HIV associated renal disease [39].
more subtle decrease in the incidence of ESRD related to
Also two African Americans with HIV associated renal
HIV, which reached a plateau at approximately 800 to
impairment exhibited marked improvement after initia-
900 new cases per year in the United States.
tion of antiretroviral drugs [40]. Notwithstanding the
Schwartz and colleagues also showed that the intro-
impact of antiretroviral therapy on HIV associated renal
duction of HAART has had a significant impact on the
disease is not without its problems. Reports have asso-
epidemiology of HIV-related kidney disease, the decline
ciated some antiretroviral drugs with renal toxicity which
in the incidence of HIV-related ESRD after the introduc-
manifested as acute renal failure, Fanconi’s syndrome,
tion of HAART strongly suggested a role for antiretro-
viral therapy in the treatment of HIVAN [29]. This is nephrogenic diabetic insipidus as reviewed bellow.
further supported by reports of clinical and histological
improvement in kidney function and architecture after
4. Antiretroviral Induced Renal Toxicity
the initiation of HAART [30,31] and by retrospective Regardless of the impact of antiretroviral drugs on ame-
cohort studies [32]. A number of cohorts have shown liorating HIV associated renal disease reports from some
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quarters have associated some antiretroviral agents with and lopinavir are reported to have good renal profile due
renal toxicity. One of the classes of antiretroviral drugs low volume of reports or lack of reports [60]. The non-
with this attribute is the protease inhibitors with respect nucleoside reverse transcriptase inhibitors: nevirapine,
to indinavir probably due to volume of reports. One of efavirenze, and delavirdine have safe renal profile as
these reports is a cohort reported by Herman which in- reported [61]. Nevertheless few cases of Fanconis like
volved 781 patients exposed to indinavir for a median syndrome and acute renal failure associated with didano-
duration of 53 weeks which revealed an incidence of 7 sine, stavudine, lamivudine, and abacavir have been re-
per 100 persons per year [41]. This is in agreement with ported [62-65].
the work of Dieleman et al (2002) [42] who in acohort of Another family of antiretroviral drugs that is asso-
1219 involving 644 patients exposed to indinavir re- ciated with nephrotoxicity is the nucleotide reverse tran-
ported an incidence of 8.3 per 100/year vs 0.8 per/year scriptase inhibitors family: Adefovir, cidofovir and teno-
for other PIs on renal toxicity while Kopp et al. (2001) fovir. They differ from the nucleoside reverse transcrip-
[43] reported 3.4% for indinavir associated renal toxicity. tase inhibitors due to the presence of a cyclic mono
A retrospective analysis of 106 HIV infected patients phosphate component. Cidofovir and adefovir are neph-
exposed to indinavir revealed (18.6%) had sustained ele- rotoxic, their accumulation in proximal tubular cells and
vation of creatinine [44]. This is consistent with18 % cytotoxicity may cause direct cytotoxic effects on the
(renal failure) reported by Voigt in a study that involved renal system [66-69]. Adefovir is currently not approved
72 patients exposed to indinavir. Merck and co (1997) by USA Food and Drug Administration.
reported incidence within the range of 2.6% - 5% in 2200
patients and 7% when doses exceed the recommended 5. Tenofovir Renal Toxicity: Evaluation of
clinical dose [45]. An incidence of 8% out of 240 pa-
tients exposed to indinavir was reported by Kopp et al.
Case Reports
(1997) [46]. In our previous study we evaluated tenofovir associated
In some studies higher incidence of indinavir asso- renal toxicity with emphasis on cohorts, clinical studies
ciated renal toxicity were reported. One of these studies and its reversibility. In this second part emphasis is on
reported incidence of crystalluria as 67% which later the evaluation of individual case reports, implications of
decreased to 25% after 2 weeks of therapy in a study drug-drug interactions, involvement of genetic factor and
which exposed 54 HIV patients to indinavir [47]. An the pharmacology of tenofovir associated renal toxicity.
incidence of 23.6% was reported over 2 years in 555 pa- Tenofor is associated with Fanconi’s syndrome which
tients exposed to indinavir [48]. A review of 214 patients results from generalized dysfunction of the proximal ren-
on indinavir-containing regimens with a median follow al tubule leading to impaired re absorption of amino ac-
up period of 216 (150 - 312) weeks almost half of the ids, glucose, urate, bicarbonate, and phosphate and in-
patients had significant loss of renal function that was creased excretion of these solutes into the urine [70].
associated with prolonged use of indinavir. Leukocyturia Fanconi’s syndrome can either be inherited or acquired.
(51.9%) was the most common finding of indinavir-as- Inherited forms occur in a number of genetic disorders
sociated renal complications [49]. Some authors have such as, hereditary, tyrosinemia, hepatorenal, cystinosis,
equally linked indinavir withacute andchronic renal fail- Lowe syndrome, galactosemia, fructose intolerance gly-
ure [50-53]. cogen storage disease type 1 and Wilson’s disease [71-
Some studies have shown that atazavavir a member of 76]. It can also be acquired through heavy metal expo-
the PIs family could be associated with renal toxicity but sure, multiple myeloma, and immunologic disorders [77,
only few cases have reported. This could be buttressed 78]. Acquired Fanconi’s syndrome has also been asso-
by a retrospective study involving 1,134 patients who ciated with the use of a number of medications including
received ritonavir-boosted atazanavir and only 11 cases aminoglycosides [79]. One of the medications reported to
of atazanavir-associated nephrolithiasis were diagnosed be associated with fanconi’s syndrome is tenofovir con-
[54]. Similarly, 30 cases of atazanavir-induced nephroli- taining antiretroviral regimens and quite a number of
thiasis were recorded without chronic renal failure over a case reports have been documented.
four-year study period [55]. Interstitial nephritis with We will start by looking at Kapadia et al. 2013 [80]
acute renal failure was described in association with ata- who presented a case of Fanconi’ s syndrome in a HIV
zanavir or atazanavir/tenofovir therapy [56]. Ritonavir is patient treated with tenofovir containing antiretroviral
always used as a booster for other protease inhibitors, it regimens characterized by eleveated levels of albuminu-
is said to have a safe renal profile probably due few re- ria and glycosuria with low serum phosphate level.
ported cases of reversible renal failure and decline in Another case was presented by Irizarry-Alvarado et al.,
renal function associated with it [57-59]. Other members 2009 [81] in which laboratory results suggested proximal
of the PI family: nelfinavir, imprenavir, fosamprenavir tubular damage consistent with Fanconi’s syndrome due
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to the following manifestations: hyperchloremic, non- developed acute renal failure and fanconis syndrome
anion gap metabolic acidosis; hypouricemia; hypophos- characterized by severe metabolic acidosis and acretinine
phatemia; and normoglycemic glycosuria. Mathew and clearance of 9.8 mg/dl [87].
Knaus reported another case of Fanconis syndrome cha- Schaaf and co in 2003 [88] also reported a case of ren-
racterisedby hyperchloremic, non-anion gap metabolic al failure a HIV patient switched to 3TC/d4T/TDF/LOP-
acidosis, hypouricemia, hypophosphatemia and glycosu- RTV from an initial antiretroviral regimen due to lack of
ria. The presence of urine osmolality, polydipsia and adherence and virological failure. Biochemical evalua-
polyuria gave credence to nephrogenic diabetes insipidus tion revealed impaired biomarkers of renal function.
assumed to be related to tenofovir use [82]. Some scho- Renal biopsy showed a mild interstitial infiltrate consist-
lars presented 7 cases of renal injury associated with te- ing of lymphocytes, focal atrophic changes in cortical
nofovir therapy which are consistent with Fanconi’s syn- tubules, luminal ectasia and loss of brush border in tu-
drome. Observations revealed proximal renal tubular bules. The authors attributed this renal failure to tenofo-
acidosis, normoglycemic glycosuria, hematuria, hypo- vir but could there be potentiation of acute renal failure
phosphatemia, hypouricemia, hypokalemia, aminoacidu- by lopinavir-rotinavir due to reported cases of nephro-
ria, citrullinuria and proteinuria. In one of these cases toxicity by these agents.
renal biopsy revealed tubulointerstitial nephropathy with Patel et al. 2007 [89] added their voices by reporting a
primary lymphocytic infiltrate [83]. case of renal failure in HIV positive patient who was
Another study presented a HIV patient who was into- treated with some antiretroviral drugs but later switched
lerant to some antiretroviral drugs and had persistent to 3TC/EFV/TDF. Biochemical evaluation revealed im-
virological failure was placed on a new therapeutic regi- balance in renal biochemical parameters which was at-
men containing tenofovir, guided by resistance testing. tributed to tenofovir. Renal biopsy showed sclerosed
Due to patient’s case presentation, laboratory analysis glomeruli with ischemic injury including portal collapse
showed hyperlactatemia, metabolic acidosis, proteinuria, of the capillary loops. Histopathological changes in glo-
glucosuria, aminoaciduria and elevated serum creatinine meruli include mild mesangial proliferation, increased
which is suggestive of Fanconi’s syndrome [84]. Another mesangial matrix and thickened capillary loops. Mod-
case of tenofovir induced Fanconi’s syndrome in a HIV erate degenerative tubular changes, loss of tubular mass,
patient was reported by creput and colleagues. Fanconi’s interstitial scarring and scattered cellular infiltrates were
syndrome was diagnosed on the basis of the presence of observed. This observation is similar to the work of Lee
metabolic acidosis, glycosuria, phosphaturia, proteinuria et al. [90] entitled acute tubular necrosis in a patient re-
and hypouricemia. Urinary cytology revealed large amounts ceiving tenofovir. Collectively they reported tenofovir
of desquamated cells of apparent tubular origin at various attributed renal impairment associated with increase cre-
stages of degeneration, varying from cells with pyknotic tinine clearance. They further supported their work by a
nuclei to anucleate cells and cytoplasmic fragments. confirmatory renal biopsy which revealed severe tubular
There were also rare clusters of mildly atypical squam- necrosis with mild degree of interstitial fibrosis and
ous cells, and no evidence of crystals. Renal biopsy re- patchy mild tubular atrophy. In 2006 Zimmermann and
vealed lesions that were largely localized in the proximal co workers [91] reported five cases of HIV positive pa-
convoluted tubules. There was generalized necrosis and tient with acute renal failure and Fanconi’s syndrome
sloughing of tubular cells, with denuding of the tubular associated with tenofovir containing antiretroviral regi-
basement membrane. When present, the tubular cell cy- mens. In these patients acute tubular necrosis was identi-
toplasm appeared thin and often vacuolated. Surrounding fied by urinary sediment with pigmented granular casts.
the tubules was focal interstitial inflammation of mixed Renal biopsy revealed unique lesions due to karyomegaly
character, without significant destruction of tubular base- in proximal tubular nuclei. Similar incidence of tenofovir
ment membranes [85]. associated Fanconi’s syndrome, nephrogenic diabetes
Some case reports showed that tenofovir could induce insipidus, and acute renal failure was reported by Ver-
renal failure and Fanconi’s syndrome simultaneously. helst et al., 2002 [92].
One of these case reports was reported by Olea and oth- Karas and colleague reported 3 cases of renal toxicity
ers in a patient on TDF/LOP-RTV containing regimens. associated with tenofovir. Renal failure, proximal tubular
Laboratory evaluation revealed glycosuria, aminoacidu- dysfunction and nephrogenic diabetes insipidus were
ria, hyperuricosuria, protenuria, hypercalciuria. This was observed. In 2 of the 3 cases, renal biopsy revealed se-
supported by renal biopsy which revealed acute focal vere tubular necrosis with characteristic nuclear changes
tubule interstitial nephritis with focal tubular atrophy and [93]. Another episode of acute renal failure in collabora-
necrosis [86]. Similar observation was reported by Ka- tion with Fanconis’s syndrome was made public by Gas-
pitsinou and Ansari who presented a case of a HIV pa- par and friends. Their observation was characterized by
tient on tenofovir containing antiretroviral regimen who glucosuria, aminoaciduria, phosphaturia, calciuria and
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uricosuria, hyperchoremic metabolic acidosis and hypo- aminiglycosides induced renal histopathological changes
kalemia [94]. This observation is in agreement with re- was characterised by glomerular congestion, glomerular
ports of similar incidence by some authors [95-97]. degeneration, loss of bowman’s capsule space, necrotic
changes inform of pale cytoplasm, pkynosis, karyolysis
6. Implications of Drug-Drug Interactions in and cellular infiltration in the cortex. Other histopatho-
Tenofovir Renal Toxicity logical changes include basal membrane interruption,
mesangial proliferation and apoptosis, indicated by de-
Drugs are been co administered to increase pharmaco-
creases in glomerular filtration and alteration in intrag-
logical or therapeutic benefits which has been proven in
lomerular dynamics [119-121]. Despite few reported
human and animal studies. It is also known that com-
cases the co administration of tenofovir and aminiglyco-
bined use of multiple drugs may cause toxicological ef-
sides should be done with caution especially in patients
fects as a result of drug-drug interactions which could be
with HIV induced tuberculosis. It is biologically possible
pharmacodynamic or pharmacokinetic interactions [98].
that aminoglycosides and tenofovir associated nephro-
Antiretroviral regimens contain 3 - 4 drugs which could
toxicity may be synergistic in the mitochondria of prox-
be administered with other drugs in the presence of co
imal tubular cells, one suggestive clinical approach is
morbidity. There are reported cases of interactions in- that the combination could be used, but with close moni-
volving antiretroviral drugs and other drugs and one of toring of renal function parameters.
these interactions is with non steroidal anti-inflammatory Furthermore synergistic or additive nephrotoxicity can
drugs (NSAIDs). Cases of renal failure associated with arise from antiretroviral-antiretroviral interactions. One
Fanconi’s syndrome in HIV patients on tenofovir con- of the suspected interactions is between tenofovir and the
taining antiretroviral drugs and NSAIDs have been re- protease inhibitors family. Some scholars observed that
ported [99]. Bicket and colleague reported that drug-drug most patients who developed nephrotoxicity associated
interaction involving diclofenac could exacerbate teno- with tenofovir received protease inhibitors [122]. In the
fovir acute kidney injury. They drew their conclusion early part of this study we vividly explain protease inhi-
from a cohort involving 89 patients on diclofenac of bitors associated nephrotoxicity with more tribute to in-
which 61 patients were treated with tenofovir. They ob- dinavir due to available literature. The treatment guide-
served that 13 patients (14.6%) developed renal impair- line for HIV management allows the co administration of
ment [100]. This is in agreement with reports from some tenofovir and boosted indinavir [123]. Only few cases of
quarters on NSAIDS induced renal toxicity in humans atazanavir induced renal toxicity have been reported as
[101-105]. In animal studies NSAIDs associated nephro- earlier explain in our work but in vitro studies, have
toxicity was characterized by glomerular degeneration, shown that atazanavir is an inhibitor and inducer of
tubular necrosis, mild interstitial inflammation, glome- P-glycoprotein and an inhibitor of cytochrome P450 3A
rulo-nephritis with several proximal convoluted tubules activity. This may potentiate the pharmacological profile
having attenuated and necrotic epithelium. These NSA- of some drugs [124]. This can be supported by a report
IDs induced morphological changes are similar to re- which showed that coadministration of tenofovir with
ported tenofovir induced renal changes in animals [106- atazanavir could increase the pharmacokinetic parame-
110]. It was also reported that incidence of acute renal ters of tenofovir and requires patient monitoring [125,
failure associated with NSAIDS account for 15.5% of all 126]. In June 2004, Gilead revised the package insert to
cases of drug induced acute renal failure hence combina- include monitoring for adverse effects in patients receiv-
tion of tenofovir with other drugs with nephrotoxic po- ing tenofovir in combination with atazanavir or lopina-
tentials should be avoided [111]. Another case of drug- vir-ritonavir associated with increased tenofovir concen-
drug interaction that could induce additive, synergistic or trations, as well as the potential for the development of
potentiate nephrotoxicity is between antiretroviral drugs ARF and Fanconi syndrome.
and aminoglycoside class of antibiotics. HIV is always Didanosine is said to be associated with renal toxicity,
associated with co morbidity like tuberculosis that may an early case report by Crowther et al. 1993 [127] de-
require co administration of antiretrovirals and aminog- scribed didanosine induced Fanconi’s syndrome and
lycosides. Recent report showed that tenofovir/strepto- nephrogenic diabetes insipidus. Some scholars also have
mycin and tenofovir/ kinamycin induced renal toxicity in attributed antiretroviral induced renal toxicity to didano-
HIV patients with tuberculosis [112]. Aminoglycosides sine [128]. Didanosine has been clinically used with te-
antibiotics are known to be associated with renal toxicity. nofovir and there are reported cases of renal toxicity at-
Some scholars have reported an incidence of 20% - 50% tributed to their co administration [129-131]. Literature
for aminoglycoside associated renal toxicity [113,114]. showed that coadministration of tenofovir and didanosine
In humans aminoglycoside can alter the function and have resulted in a significant increase (28%) in maxi-
architecture of the kidney [115-118]. In animal studies mum serum concentrations of didanosine, leading to an
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increased risk of didanosine toxicity [132]. Didanosine is function is warranted for these patients [140]. Similar
taken up by hOAT1 at the proximal tubules, and it is observation was reported by Izzedine et al. who assess
possible that competition between tenofovir and didano- the influence of single-nucleotide polymorphisms (SNPs)
sine for the hOAT1 transporter produces an increase in identified in ABCC2 and ABCC4. They were able to ob-
the didanosine concentration, leading to an increased risk servethat ABCC2 haplotypes are associated with rPT
of mitochondrial damage and nephropathy. induced by TDF in HIV-1-infected patients. No associa-
In vitro experiments in renal proximal tubule cells tion was observed between ABCC4 polymorphism and
have recently shown that didanosine may be very toxic TDF-induced rPT in the present study [141].
and had negative effects on mitochondrial DNA and cy- Pushpakom et al. also explored the association of
tochrome oxidase II mRNA. This effect was enhanced in ABCC10 transports andABCC10 single-nucleotide poly-
the presence of tenofovir, suggesting that didanosine morphisms (SNPs) with tenofovir induce KTD. They
cellular clearance was inhibited [133,134]. Moreover, reported that tenofovir is a substrate for ABCC10, and
administration of didanosine to patients also receiving genetic variability within the ABCC10 gene may influ-
tenofovir may increase the risk of tenofovir-associated ence tenofovir renal tubular transport and contribute to
proximal tubulopathy and nephrogenic diabetes. the development of KTD [142]. The association between
tenofovir-induced KTD and 14 single nucleotide poly-
7. Impact of Genetic Polymorphism on morphisms (SNPs) in the ABCC2, ABCC4, ABCC10,
Tenofovir Renal Toxicity SCL22A6, and ABCB1 genes was investigated in 190
TFV-associated kidney tubular damage (KTD) is multi- Japanese patients, by Nishijima et al., [143] in this study
factorial with risk factors including polymorphisms along they acknowledge the association between SNPs in
with nongenetic factors, such as age, and body weight ABCC2 and tenofovir-induced KTD in an Asian popula-
[135,136]. One of these risk factors that have captured tion. These reports leave more rooms for questions, do
attention is the genetic factor which must have intro- the African-American population habour genetic poly-
duced dichotomy in the distribution of HIV associated morphism that is vulnerable or predispose to tenofovir
renal damage between the black and the white popula- associated renal damage? This calls for more evaluations.
tion.Reports have shown incidence of higher HIV asso-
ciated renal damage especially HIVN among African- 8. Possible Pharmacology of Tenofovir Renal
Americans while higher incidence of immune complex- Toxicity
mediated glomerulonephritis occurred among the whites. The mechanisms of drug induced renal toxicity can vary
This is supported with Data from the US Renal Database largely based on the pharmacologic action, metabolism,
System (USRDS) which revealed that renal disease at- and ultimate pathway of excretion of the administered
tributed to HIVAN recorded in the US nearly 90% are drug. Although several recent studies have revealed the
reported in African-Americans [137]. This is consistent nephrotoxicity of tenofovir, but the mechanism of teno-
with another report from the Veterans Affairs Medical fovir nephrotoxicity is not clear. Studies have suggested
System which showed a higher incidence of end-stage that mitochondrial damage may play an important role in
renal disease among HIV-infected African-Americans TDF induced renal damage [144].
which may suggests genetic predisposition in HIV asso- Researchers have shown that tenofovir is eliminated in
ciated renal disease [138]. A similar incidence of higher the kidney by glomerular filtration and tubular secretion.
end- stage renal disease in blacks was also reported in a Circulating tenofovir is absorbed from the bloodstream
single-center study from Johns Hopkins, with an 18-fold into the proximal tubule cells by the renal organic anion
higher risk for progression to ESRD among HIV infected transporters (hOATs) 1 and 3. Efflux from these cells
African-Americans compared with HIV-infected Cauca- into the tubular lumen is mediated by the multidrug re-
sians [139]. The genetic basis of this disparity was fur- sistance protein (MDR)-4 [145]. The hOATs may gener-
ther elucidated by Rodrigues-Nova and co who explored ate high intratubular tenofovir concentrations that may
the association between kidney tubular dysfunction and interfere with the replication of mitochondrial DNA
polymorphisms in genes encoding drug transporters. [146]. Interference with the function of mitochondria can
They reported that approximately 17% of HIV-infected be supported by some animal studies in which adminis-
patients treated with tenofovir had kidney tubular dys- tration of TDF 100 mg/kg/day revealed enlargement of
function homozygosity for the C allele at position −24 of mitochondria and disruption of mitochondria crystal in
the ABCC2 gene which is strongly associated with KTD rats [147]. A study in which HIV + transgenic mice and
in this population. This polymorphism may help to iden- their wild-type littermates were exposed to tenofovir,
tify patients at greater risk for developing tenofo- renal proximal tubules showed ultrastructural mitochon-
vir-associated tubulopathy, and close monitoring of renal drial abnormalities and decreased mtDNA levels, which
OPEN ACCESS PP
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Pharmacology & Pharmacy, 2014, 5, 97-111

Published Online January 2014 (http://www.scirp.org/journal/pp)

Tenofovir Renal Toxicity: Evaluation of Cohorts and

1. Introduction neous cells. It is the major organ of excretion and ho-

paralleled the ultrastructural mitochondrial abnormalities REFERENCES

pp. 3824-3832. http://dx.doi.org/10.1128/AAC.00437-06 scriptase Inhibitors,” Antimicrobial Agents and Chemo-

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