HAART AND KIDNEY
Nephrology Grand Rounds
Tuesday, December 22nd 2009
Aditya Mattoo
Outline
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HIV Life Cycle
Antiretroviral
Pharmacokinetics
Dosing Adjustments in Kidney Disease
Antiviral Renal Tubular Handling
Antiretroviral Renal Toxicities
Indinavir Crystalluria
Tenofovir Nephrotoxicity
HIV Life Cycle
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HIV is internalized by binding to
CD4 surface receptors on T cells.
HIV RNA is released from
nucleocapsid, then RT copies
genomic RNA into proviral DNA.
Proviral DNA is then inserted into
host cell DNA.
The inserted HIV genome is
transcribed into RNA, including new
proviral RNA that will be
packaged into new virions as viral
RNA.
Other RNA are translated into viral
capsid and regulatory proteins.
Post-translational cleaving of
polyproteins by viral protease.
Viral RNA is packaged in new
capsid envelopes and released
from the cell as newly formed
infectious virions.
Berns et al. HAART and the kidney: An update on antiretroviral medications
for nephrologists. CJASN, 1:117-129, 2006.
ANTIRETROVIRALS
Antiretrovirals
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Initial HAART regimens include combinations of
drugs from at least two different of the three major
classes of antiretroviral agents.
The new fusion inhibitor, enfurvirtide, and the new
integrase inhibitor, raltegravir, are not
recommended as part of an initial HAART regimen
at this time.
Many ART agents are eliminated at least partly by
the kidneys and require dosage adjustments in
patients with reduced GFR.
Protease Inhibitors
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Primarily metabolized in the liver
Urinary excretion accounts for 10% of clearance for indinavir and <5% for
other drugs in this class.
PIs are highly protein bound, most being >90% protein bound in serum,
however indinavir is approximately 60% protein bound.
Not cleared by any significant extent by HD or PD.
None of the currently available PI requires dose adjustment for patients with
impaired kidney function.
Nucleoside vs Nucleotide Structure
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NRTI and NtRTI is essentially the same; they are analogues of the naturally
occurring deoxynucleotides needed to synthesize the viral DNA and they compete
with them for incorporation into the growing viral DNA chain.
NNRTI block reverse transcriptase by binding at a different site on the enzyme,
compared to NRTIs and NtRTIs.
NNRTIs are not incorporated into the viral DNA but instead inhibit the movement of
protein domains of reverse transcriptase that are needed to carry out the process
of DNA synthesis (i.e. non-competitive inhibition).
Nucleoside Reverse Transcriptase Inhibitors (NRTI)
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All of the NRTI except abacavir require dosage
adjustment in patients with impaired kidney function
and in patients on dialysis.
NRTI are small molecules with volumes of distribution of
0.5 to 1.9 L/kg with low protein binding (4 to 38%).
Abacavir and to a lesser extent zidovudine are
metabolized in the liver to inactive metabolites.
Urinary excretion of parent drug is 1% for abacavir,
15-20% for zidovudine and 30-70% for the other
NRTI.
For many of the NRTI urinary excretion is by both
filtration and tubular secretion.
NRTI and NtRTI
Combination NRTI
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It is recommended that fixed dose combinations of NRTI
should not be administered in patients with impaired
renal function.
Instead, the medications should be administered
separately so that appropriate dosage adjustments are
made for each individual agent.
Entry/Fusion Inhibitors
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Enfuviritide (Fuzeon), is the only available fusion
inhibitor.
It is administered by injection and his highly protein
bound (approximately 92%).
Pharmacokinetic studies in patients with impaired
renal function has not been performed, but
clearance of the drug seems not to be altered as
per case reports.
Leen C et al. Phamacokinetics of enfurviritide in a patient with impaired renal
function. Clinical Infectious Dieseases 39:e119-e121, 2004.)
Integrase Inhibitor
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Raltegravir (Insentress), approved in 2007, is the only
available integrase inhibitor.
It has only been studied in patients with limited
treatment options (HIV strains with triple-class drug
resistance) and was demonstrated to have a better viral
suppression as compared to placebo.
Administered orally, with approximately 85% of drug is
protein bound in serum.
No dosage adjustment needed in renal impairment as
the drug is primarily metabolized by the liver.
No studies have been performed to determine
clearance of the drug with dialysis.
Stiegbigel et al. Raltegravir with optimized background therapy for resistant HIV-1
infection. NEJM, 359:339-354, 2008.
ANTIVIRAL RENAL TUBULAR
HANDLING
Renal Tubular Drug Transporters
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Over the past decade, considerable progress in the molecular
identification and characterization of transporters involved in the
renal tubular handling of drugs.
These transporters belong to different families, the main ones are:
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Organic anion transporters (OAT)
Organic cation transporters (OCT)
P-glycoprotein (Pgp)
Multidrug resistant-associated protein transporters (MRP)
Peptide transporters (PEPT).
Drug accumulation in the renal tubular cells are dependent on the
equillibrium of uptake at the basolateral membrane (BLM) and the
efflux at the apical brush border membrane (BBM).
Treatments that block the efflux, like those that enhance uptake may
thus increase both accumulation and toxicity of the drug.
Renal Tubular Drug Transporters
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Uptake of OA across the BLM is mediated
by a Na-dependent OAT system.
OAT1 exchanges intracellular αketoglutarate (αKG2) against extracellular
organic anions, thereby driving organic
anion uptake against the prevailing
electrochemical potential difference with
Na-αKG2 cotransport via the
sodium/dicarboxylate cotransporter (e.g.
NSAIDs).
The BBM contains various transport systems
for efflux of OA into the lumen or
reabsorption from lumen into the cell.
The multidrug resistance transporter, MRP2,
mediates primary active luminal secretion.
Cellular uptake of OC across the BLM is
mediated by OCT (e.g. antihistamines and
antiarrhythmics).
Secretion of cellular OC across BBM is
mediated primarily by P-glycoprotein.
PEPT1 and PEPT2 mediate luminal uptake of
peptide drugs (e.g. batalactamases).
Launay-Vacher et al. Renal tubular drug transporters. Nephron Physiology, 103:p97-106, 2006.
Antiviral Drugs and Renal Tubular Transporters
Izzedine et al. Renal tubular transporters and antiviral drugs: an update. AIDS, 19:455-462, 2005.
NEPHROTOXICITIES OF ART
NRTI and Lactic Acidosis
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NRTI have been associated with disturbances in
lactic acid homeostasis with presentations ranging
from asymptomatic chronic hyperlactemia to acute,
life-threatening lactic acidosis.
Although first described with didanosine, it more
commonly occurs with zidovudine.
All NRTI have been implicated, with dual NRTI
therapies having an increased risk for lactic
acidosis.
Pathogenesis of NRTI Lactic Acidosis
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Believed to be related at least in part to inhibition
of mitochondrial DNA polymerase by intracellularly
generated triphosphate metabolites of these drugs.
Inhibition of hepatic mitochondrial DNA synthesis is
thought to lead to impaired mitochondrial ATP
synthesis, ATP depletion, and impaired oxidative
phosphorylation with increased lactic acid
production.
Incidence of NRTI Lactic Acidosis
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Approximately 20-30% of patients on NRTI can be
found to have asymptomatic hyperlactemia (levels
< 2.5 mmol/L) without acidemia.
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Severe lactic acidosis (levels > 5 mmol/L) is much
rarer occurring in 1.5-2.5% of patients.
Prognosis of NRTI Lactic Acidosis
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Treatment is often continued in patients with
asymptomatic hyperlactemia without progression to
severe lactic acidosis.
Severe lactic acidosis necessitates discontinuation of
offending medications.
Hyperlactemia may persist for several weeks after
discontinuation of NRTI.
Mortality rates with severe lactic acidosis secondary
to NRTI approach 80%.
Nephrotoxicity of HAART
Said et al. Nephrotoxicity of antiretroviral therapy in an HIV-infected patient. KI 71:1071-1075, 2007.
INDINAVIR CRYTALLURIA
Indinavir Crystalluria
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Associated with crystalluria, nephrolithiasis and
obstructive AKI.
Asymptomatic crystalluria occurs in up to two-thirds of
treated patients.
Sterile pyuria, microscopic hematuria and low-grade
proteinuria can also be seen in asymptomatic
individuals.
Symptomatic crystalluria/nephrolithiasis can occur at
any point after drug initiation and presents with typical
symptoms of flank pain, dysuria and gross hematuria.
Elevations in serum creatinine levels, can also be seen in
up to 20% of treated individuals.
Indinavir Crystalluria
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As mentioned earlier, indinavir is primarily
metabolized in the liver with only 10% renal
excretion.
Indinavir is highly soluble in acidic urine (100mg/ml
at pH 3.5) but relatively insoluble in more alkaline
urine (0.3mg/ml at pH 5.0) which predisposes
crystal formation at typical urine pH levels.
Crystals are of varying shapes composed primarily
of indinavir monohydrate, but calcium oxalate and
calcium phosphate may also be present.
Most are radiolucent and not detectable with plain
radiographs.
Berns et al. HAART and the kidney: An update on antiretroviral medications for nephrologists. CJASN, 1:117-129, 2006.
Light Microscopy of
Urinary Sediment
A. Rectangular plates of various sizes
containing needle-shaped crystals. The
plates have irregular borders with
occasional tapering and present an
internal layering more evident in the
largest forms (large arrows). Many
crystal fragments are seen in the
background; small, triangular pieces
(small arrows) represent broken ends of
the needles.
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B. The frequent, typical configuration
of indinavir crystals in a sheaf of
numerous densely packed needles.
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C. Several indinavir crystal groupings
arranged in a rosette.
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Indinavir Renal Biopsy
Light Microscopy
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Three tubules containing
abundant clear intraluminal
crystals with needle and rod
shapes surrounded by
mononuclear cells and giant
cells. Adjacent interstitial
contains a dense infiltrate on
mononuclear leukocytes.
High power view with clear
intratubular crystals engulfed
by intraluminal giant cells.
TENOFOVIR
NEPHROTOXICITY
Tenofovir Nephrotoxicity
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Because of its once daily dosing and coformulation in
combination pills, tenofovir (TDF) is the most widely
prescribed antiretroviral medication.
It is one of three monophosphate nucleoside analogs (the
others are adefovir and cidofovir approved for the
treatment of HBV and CMV, respectively).
In 2002, the first case report of TDF causing AKI, Fanconi
syndrome and nephrogenic DI in a patient was published.
Onset is typically within 5-12 months after initiating
therapy and complete recovery is often seen within several
months after discontinuation.
Lactic acidosis has also been described (also seen with
other NRTI).
Verlhelst D, et al. Fanconi syndrome and renal failure induced by tenofovir: A first case report. AJKD 40:1331-1333, 2002.
Tenofovir Nephrotoxicity Biopsy Findings
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Cytoplasmic vacuolization
Apical localization of tubular cell nuclei
Reduction in brush border on proximal tubular cells
Labarga et al.
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284 consecutive HIV patients were examined, 154
of TDF (group 1), 49 on other HAART regimens
(group 2) and 81 drug-naïve (group 3).
Tubular damage was defined as nondiabetic
glucosuria, hyperaminoaciduria and
hyperphosphatemia.
Proportion of patients with tubular damage in
groups 1, 2 and 3 were 22, 6 and 12%,
respectively.
Labarga et al. Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir. AIDS,
23:689-696, 2009.
Labarga et al.
Liborio et al.
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Liborio et al. suspected that down regulation of a variety
of ion transporters were responsible for tenofovir side
effects and could be corrected with the administration of
rosiglitazone.
Rosiglitazone is a peroxisome proliferator-activated
receptor- (PPAR-) agonist.
PPAR- is a member of the nuclear receptor superfamily
of ligand-activated transcription factors.
By binding to the peroxisome proliferator response
element on DNA, PPAR- regulates the transcription of
numerous target genes including expression of Na-K-2Cl
cotransporter (NKCC2), Na/H exchanger 3 (NHE3), NaPhosphate cotransporter subtype IIa (NaPi-IIa) and
aquaporin 2 (AQP2).
Liborio et al. Rosiglitazone reverses tenofovir-induced nephrotoxicity. KI, 74:910-918, 2008.
Liborio et al.
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Rats were fed a diet either with Hi-TDF doses
(300mg/kg) alone for 30 days or Hi-TDF diet for
30 days + rosiglitazone (RSG) on days 16-30.
Similarly, the Lo-TDF arm involved rats fed for 30
days with a diet containing low doses of TDF
(50mg/kg) as well as Lo-TDF + Rosiglitazone (RSG)
group.
Hemodynamic measurements were obtained at 30
days as well as urine and serum parameters.
Tenofovir and Hemodynamics
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The rats in the Hi-TDF group presented with higher
blood pressure and significantly impaired renal
function.
Accompanied by intense renal vasoconstriction (as
evidenced by reduced renal blood flow and
increase renal vascular resistance)
In addition, the Hi-TDF group rats had markedly
lower eNOS expression than the corresponding
control rats.
Tenofovir and Hemodynamics
Tenofovir and eNOS expression
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Semiquantitative immunoblotting
of kidney fractions with antieNOS.
Densitometric analysis of all
samples from control, Hi-TDF, and
Hi-TDF + RSG rats. The Hi-TDF
rats presented with decreased
endothelial nitric oxide synthase
expression. Levels of eNOS
expression improved in response
to RSG.
*P<0.001 vs control and Hi-TDF
+ RSG group.
Tenofovir and Tubular Dysfunction
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Tenofovir administration
was associated with
increased UOP, lower
Uosm, higher urinary
phosphorus excretion
and lower serum
bicarbonate.
TDF + rosiglitazone
corrected all of these
parameters with Uosm
actually significantly
higher than control.
TDF and NaPi-IIa Cotransporter
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Tubular absorption of
phosphorus is largely performed
in the proximal tubules via NaPi-IIa cotransporter.
The Lo-TDF group rats had
decreased expression of NaPiIIa.
Levels were completely restored
in response to rosiglitazone
(RSG) explaining the
normalization of phosphaturia
observed.
TDF and NHE3 expression
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Rats treated with TDF had lower
serum bicarbonate and serum pH
levels when compared to controls
with low urine pH as well.
The authors thought to investigate
the cause of the serum acidosis by
measuring Na/H exchanger 3
(NHE3) is the principle agent of
bicarbonate generation and
reabsorption.
The Lo-TDF group rats presented
decreased expression of NHE3
which were completely restored in
response to RSG.
TDF and Aquaporin 2 expression
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As UOP was higher with
lower Uosm in TDF
treated rats, Liborio et al
investigated the
expression of AQP2 in the
distal tubule.
Levels of AQP2
expression were
completely restored in
response to RSG, also
increasing in relation to
controls.
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