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HAART and Kidney. Nephrology Grand Rounds Tuesday, December 22 nd 2009 Aditya Mattoo. Outline. HIV Life Cycle Antiretroviral Pharmacokinetics Dosing Adjustments in Kidney Disease Antiviral Renal Tubular Handling Antiretroviral Renal Toxicities Indinavir Crystalluria

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HAART and Kidney

Nephrology Grand Rounds

Tuesday, December 22nd 2009

Aditya Mattoo

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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

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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, 1:117-129, 2006.

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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.

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Protease Inhibitors

  • 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.

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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).

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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.

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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.

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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 39:e119-e121, 2004.)

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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, 359:339-354, 2008.

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Antiviral renal Tubular handling

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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.

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Renal Tubular Drug Transporters

  • Uptake of OA across the BLM is mediated by a Na-dependent OAT system.

  • OAT1 exchanges intracellular α-ketoglutarate (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.

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Antiviral Drugs and Renal Tubular Transporters

Izzedine et al. Renal tubular transporters and antiviral drugs: an update. AIDS, 19:455-462, 2005.

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Nephrotoxicities of ART

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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.

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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.

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Incidence of NRTI Lactic Acidosis

  • Approximately 20-30% of patients on NRTI can be found to have asymptomatic hyperlactemia (levels < 2.5 mmol/L) without acidemia.

  • Severe lactic acidosis (levels > 5 mmol/L) is much rarer occurring in 1.5-2.5% of patients.

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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%.

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Nephrotoxicity of HAART

Said et al. Nephrotoxicity of antiretroviral therapy in an HIV-infected patient. KI 71:1071-1075, 2007.

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Indinavir Crytalluria

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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.

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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, 1:117-129, 2006.

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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.

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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.

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Tenofovir Nephrotoxicity

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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 40:1331-1333, 2002.

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Tenofovir Nephrotoxicity Biopsy Findings

  • Cytoplasmic vacuolization

  • Apical localization of tubular cell nuclei

  • Reduction in brush border on proximal tubular cells

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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 nondiabeticglucosuria, 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.

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Labarga et al.

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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 peroxisomeproliferator-activated receptor- (PPAR-) agonist.

  • PPAR- is a member of the nuclear receptor superfamily of ligand-activated transcription factors.

  • By binding to the peroxisomeproliferator 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, 74:910-918, 2008.

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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.

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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.

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Tenofovir and Hemodynamics

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Tenofovir and eNOS expression

  • Semiquantitativeimmunoblotting 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.

  • *P<0.001 vs control and Hi-TDF + RSG group.

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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.

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TDF and NaPi-IIa Cotransporter

  • Tubular absorption of phosphorus is largely performed in the proximal tubules via Na-Pi-IIacotransporter.

  • 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.

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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.

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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.

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