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HAART and Kidney

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HAART AND KIDNEY Nephrology Grand Rounds Tuesday, December 22nd 2009 Aditya Mattoo Liborio et al. Rats were fed a diet either with Hi-TDF doses (300mg/kg) alone for ... – PowerPoint PPT presentation

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Title: HAART and Kidney


1
HAART and Kidney
  • Nephrology Grand Rounds
  • Tuesday, December 22nd 2009
  • Aditya Mattoo

2
Outline
  • HIV Life Cycle
  • Antiretroviral
  • Pharmacokinetics
  • Dosing Adjustments in Kidney Disease
  • Antiviral Renal Tubular Handling
  • Antiretroviral Renal Toxicities
  • Indinavir Crystalluria
  • Tenofovir Nephrotoxicity

3
HIV Life Cycle
  • 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, 1117-129, 2006.
4
Antiretrovirals
5
Antiretrovirals
  • 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.

6
Protease Inhibitors
  • Primarily metabolized in the liver
  • Urinary excretion accounts for 10 of clearance
    for indinavir and lt5 for other drugs in this
    class.
  • PIs are highly protein bound, most being gt90
    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.

7
Nucleoside vs Nucleotide Structure
  • 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).

8
Nucleoside Reverse Transcriptase Inhibitors
(NRTI)
  • 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.

9
NRTI and NtRTI
10
Combination NRTI
  • 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.

11
Entry/Fusion Inhibitors
  • 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 39e119-e121,
2004.)
12
Integrase Inhibitor
  • 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, 359339-354, 2008.
13
Antiviral renal Tubular handling
14
Renal Tubular Drug Transporters
  • 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
  • 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.

15
Renal Tubular Drug Transporters
  • Uptake of OA across the BLM is mediated by a
    Na-dependent OAT system.
  • OAT1 exchanges intracellular a-ketoglutarate
    (aKG2) against extracellular organic anions,
    thereby driving organic anion uptake against the
    prevailing electrochemical potential difference
    with Na-aKG2 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, 103p97-106,
2006.
16
Antiviral Drugs and Renal Tubular Transporters
Izzedine et al. Renal tubular transporters and
antiviral drugs an update. AIDS, 19455-462,
2005.
17
Nephrotoxicities of ART
18
NRTI and Lactic Acidosis
  • 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.

19
Pathogenesis of NRTI Lactic Acidosis
  • 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.

20
Incidence of NRTI Lactic Acidosis
  • Approximately 20-30 of patients on NRTI can be
    found to have asymptomatic hyperlactemia (levels
    lt 2.5 mmol/L) without acidemia.
  • Severe lactic acidosis (levels gt 5 mmol/L) is
    much rarer occurring in 1.5-2.5 of patients.

21
Prognosis of NRTI Lactic Acidosis
  • 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.

22
Nephrotoxicity of HAART
Said et al. Nephrotoxicity of antiretroviral
therapy in an HIV-infected patient. KI
711071-1075, 2007.
23
Indinavir Crytalluria
24
Indinavir Crystalluria
  • 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.

25
Indinavir Crystalluria
  • 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, 1117-129, 2006.
26
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.
  • B. The frequent, typical configuration of
    indinavir crystals in a sheaf of numerous densely
    packed needles.
  •  
  • C. Several indinavir crystal groupings arranged
    in a rosette.

27
Indinavir Renal Biopsy Light Microscopy
  • 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.

28
Tenofovir Nephrotoxicity
29
Tenofovir Nephrotoxicity
  • 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 401331-1333, 2002.
30
Tenofovir Nephrotoxicity Biopsy Findings
  • Cytoplasmic vacuolization
  • Apical localization of tubular cell nuclei
  • Reduction in brush border on proximal tubular
    cells

31
Labarga et al.
  • 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,
23689-696, 2009.
32
Labarga et al.
33
Liborio et al.
  • 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-activat
    ed 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), Na-Phosphate
    cotransporter subtype IIa (NaPi-IIa) and
    aquaporin 2 (AQP2).

Liborio et al. Rosiglitazone reverses
tenofovir-induced nephrotoxicity. KI,
74910-918, 2008.
34
Liborio et al.
  • 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.

35
Tenofovir and Hemodynamics
  • 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.

36
Tenofovir and Hemodynamics
37
Tenofovir and eNOS expression
  • Semiquantitative immunoblotting of kidney
    fractions with anti-eNOS.
  • 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.
  • Plt0.001 vs control and Hi-TDF RSG group.

38
Tenofovir and Tubular Dysfunction
  • 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.

39
TDF and NaPi-IIa Cotransporter
  • Tubular absorption of phosphorus is largely
    performed in the proximal tubules via Na-Pi-IIa
    cotransporter.
  • The Lo-TDF group rats had decreased expression of
    NaPi-IIa.
  • Levels were completely restored in response to
    rosiglitazone (RSG) explaining the normalization
    of phosphaturia observed.

40
TDF and NHE3 expression
  • 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.

41
TDF and Aquaporin 2 expression
  • 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.

42
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