Molecular mechanism of drug induced nephrotoxicity

EVALUATION SEMINAR ON
MOLECULAR MECHANISMS OF DRUG INDUCED
NEPHROTOXICITY.

TABLE OF CONTENTS
1. INTRODUCTION
2. TYPES OF NEPHROTOXICITY
3. BIOMARKERS FOR DRUG INDUCED RENAL DAMAGE
4. PATHOGENIC MECHANISM
5. NEPHROTOXICITY DUE TO
a) Aminoglycosides
b) Cyclophosphamide
c) Cisplatin
d) Radiocontrast
e) Analgesic
f) Amphotericin
g) Crystal forming drug
6. REFERNCE

NEPHROTOXICITY
INTRODUCTION:
Nephrotoxicity is one of the most common kidney problems and
occurs when your body is exposed to a drug or toxin that causes
damage to your kidneys.
Drugs shown to cause nephrotoxicity exert their toxic effects by
one or more common pathogenic mechanisms.

Pathophysiologic Responses
Acute renal failure
• Decline in GFR
• Azotemia
Chronic renal failure
Adaptive responses
• Compensatory increase in single nephron GFR
• Metallothionein induction
• Stress protein induction
Assessment of Nephrotoxicity
• Urinalysis: Volume, pH, Glucose, Proteins, Cells
• Blood chemistry: Blood urea nitrogen, Creatinine
• Histopathology

S.N Types Characters
1. Pseudo Renal Failure Increase BUN due to protein catabolism , Normal Cr
Eg. Steroids, tetracyclines
2. Interstitial Nephritis Form of nephritis affecting the interstitium of the kidneys
surrounding the tubules.
3. Acute Glomerulonephritis Renal disease (usually of both kidneys) characterized by
inflammation of the glomeruli, or small blood vessels in the
kidneys.
4. Crystal nephropathy Intratubular precipitation of either exogenously administered
medications or endogenous crystals (induced by certain drugs) can
promote chronic and acute kidney injury, termed crystal nephropathy.
5. Acute Tubular Necrosis Condition involving the death of tubular cells that form the tubule
that transports urine to the ureters while reabsorbing 99 of the
water.
6. Rhabdomyolysis Condition in which damaged skeletal muscle tissue , breaks down
rapidly and Breakdown products of damaged muscle cells are
released into the bloodstream some of these, such as the protein
myoglobin, are harmful to the kidneys and may lead to kidney failure.
7. Nephrotic Syndrome Characterized by a number of diseases proteinuria, hypoalbuminemia and
edema.
8. Minimal-change Disease of the kidney that causes nephrotic syndrome and usually
affects children (peak incidence at 23 years of age).
TYPES of NEPHROTOXICITY

The field of molecular toxicology has spawned new options of the detection of nephrotoxicity which
includes Kim-1, clusterin, osteopontin or RPA-1, and other transcriptional biomarkers which enable
the earlier detection of AKI.
KIM-1: Transmembrane protein expressed by tubule epithelial cells in response to injury
Elevated in response to gentamicin, mercury, chromium, cadmium
Increased mRNA expression in kidneys of rats treated with gentamicin,
Increased in renal transplant recipients and patients with acute kidney injury of
various cause
Cystatin C: Inhibitor of extracellular cysteine proteinase widely expressed by nucleated
Cells
Increased in diabetic rats and in response to subtotal or unilateral nephrectomy
Elevated during chromium nephropathy
Clusterin: In a wide range of tissue expressed secreted glycoprotein
Involved in cell adhesion, membrane recycling, tissue remodeling, cell cycle
regulation apoptosis and DNA repair
 Increased following renal ischemia, unilateral urethral obstruction or in
response to various nephrotoxins e.g., Increased mRNA expression in kidneys
of rats treated with gentamicin, cisplatin, vancomycin, bacitracin
 Over expressed in human renal diseases.
RPA-1: shows increased amount in urine and tissue after treatment of rats with BEA,
propyleneimine, and indomethacin.
BIOMARKERS FOR DRUG-INDUCED RENAL DAMAGE AND
NEPHROTOXICITY

1.ALTERED INTRAGLOMERULAR HEMODYNAMICS
Pathogenic Mechanisms
Most drugs found to cause nephrotoxicity exert toxic effects by one or more common pathogenic
mechanisms. These include altered intraglomerular hemodynamics, tubular cell toxicity,
inflammation, crystal nephropathy, rhabdomyolysis, and thrombotic microan-giopathy.
● The kidney maintains or autoregulates intraglomerular pressure by modulating
the afferent and efferent arterial tone to preserve GFR and urine output.
● Renal perfusion depends on circulating prostaglandins to vasodilate the afferent
arterioles, allowing more blood flow through the glomerulus.Intraglomerular pressure
is sustained by the action of angiotensin-II–mediated vasoconstriction of the
efferent arteriole.
● Drugs with antiprostaglandin activity (e.g., nonsteroidal anti-inflammatory drugs
[NSAIDs]) or those with antiangiotensin-II activity (e.g., angiotensin-converting
enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]) can interfere with the
kidneys' ability to autoregulate glomerular pressure and decrease GFR.

2.TUBULAR CELL TOXICITY
● Drugs that cause tubular cell toxicity do so by impairing mitochondrial function,
interfering with tubular transport, increasing oxidative stress, or forming
free radicals.
● Drugs associated with this pathogenic mechanism of injury include aminoglycosides,
amphotericin B , antiretrovirals, cidofovir, tenofovir, cisplatin, contrast dye, foscarnet,
and zoledronate.

3.INFLAMMATION
● Drugs can cause inflammatory changes in the glomerulus, renal tubular cells, and the
surrounding interstitium, leading to fibrosis and renal scarring.
● Medications that cause acute interstitial nephritis are thought to bind to antigens in the
kidney or act as antigens that are then deposited into the interstitium, inducing an
immune reaction.
● Medications such as GOLD therapy, hydralazine, interferon-alfa, lithium, NSAIDs,
propylthiouracil, and pamidronate have been reported as causative agents.

4.CRYSTAL NEPHROPATHY
● Drugs that produce crystals that are insoluble in human urine. The crystals
precipitate, usually within the distal tubular lumen, obstructing urine flow and
eliciting an interstitial reaction.
● Commonly prescribed drugs associated with production of crystals include
antibiotics (e.g., ampicillin, ciprofloxacin [Cipro], sulfonamides); antivirals (e.g.,
acyclovir, foscarnet, ganciclovir [Cytovene]); indinavir; methotrexate; and
triamterene (Dyrenium).

5. RHABDOMYOLYSIS
● Rhabdomyolysis is a syndrome in which skeletal muscle injury leads to lysis of the
myocyte, releasing intracellular contents including myoglobin and creatine kinase
into the plasma.
● Myoglobin induces renal injury secondary to direct toxicity, tubular obstruction, and
alterations in GFR.
● Many drugs of abuse, such as cocaine, heroin, ketamine (Ketalar), methadone, and
methamphetamine, have been reported to cause rhabdomyolysis.

6.THROMBOTIC MICROANGIOPATHY
● In thrombotic microangiopathy, organ damage is caused by platelet thrombi in the
microcirculation, as in thrombotic thrombocytopenic purpura.
● Mechanisms of renal injury secondary to drug-induced thrombotic microangiopathy
include an immune-mediated reaction or direct endothelial toxicity.
● Drugs most often associated with this pathogenic mechanism of nephrotoxicity
include antiplatelet agents (e.g., clopidogrel [Plavix], ticlopidine [Ticlid]), cyclosporine,
mitomycin-C (Mutamycin), and quinine (Qualaquin).

● Aminoglycosides are nephrotoxic because a small but sizable proportion of the administered
dose (≈5%) is retained in the epithelial cells lining the S1 and S2 segments of the proximal
tubules after glomerular filtration.
● Aminoglycosides accumulated by these cells are mainly localized with endosomal and
lysosomal vacuoles but are also localized with the Golgi complex. They elicit an array of
morphological and functional alterations of increasing severity.
NEPHROTOXICITY DUE TO AMINOGLYCOSIDES
Aminoglycosides bind to the brush-border membrane in their cationic form. The initial
points of attachment are probably the acidic phospholipids.
Aminoglycosides are transferred to the transmembrane protein megalin, with which they become
internalized in endosomes.
Then they are transferred from endosomes to lysosomes through the physiological process of
endosome-lysosome fusion, aminoglycosides will be exposed to a fairly acidic pH ('5), at which
they will be fully protonated and therefore expected to bind tightly to negatively charged lipid
bilayers.
The binding of aminoglycosides to lipid bilayers causes their aggregation as well as the inhibition of
the activities of phospholipases.

Cytosolic gentamicin could act directly on mitochondria. It involves mitochondrial activation
with the release of cytochrome c and activation of caspase-3.
Gentamicin also triggers the generation of ROS in vitro in the presence of polyunsaturated
lipids, which could also participate to the apoptosis process.

CYCLOSPORINE / TACROLIMUS INDUCED NEPHROTOXICITY
● Chronic cyclosporine nephrotoxicity is characterized by tubular atrophy and interstitial
fibrosis with progressive renal impairment.
● Cyclosporine causes vasoconstriction of the afferent and efferent glomerular arterioles and
reductions in renal blood flow and glomerular filtration rate (GFR).
● Renal tubular injury is a consequence of renal vasoconstriction and endothelial injury leading
to ischemia, as well as a direct toxic effect of cyclosporine A on tubular epithelium.

NEPHROTOXICITY DUE TO CISPLATIN
● Cisplatin nephrotoxicity is characterized by a reduced renal perfusion and a concentrating
defect. Cisplatin injures essentially the S1 and S3 portions of the proximal tubules and the
distal tubules.
● Cisplatin recruits the Bax-mediated mitochondrial pathway for apoptosis and activates initiator
caspases-8, –9 and –2, and executioner caspase-3 in cultured tubular cells and in vivo.
Increased expression of p53 appears critical for apoptosis induction.
● PUMA and p53-induced death domain protein (PIDD) are critical p53 targets, the expression of
which is induced by cisplatin.
● In addition, cisplatin activates the MAPKs, ERK, JNK, and p38, both in vivo and in vitro.
● Cisplatin also decreases Bcl-xL, increases oxygen radical production and increases Cdk2
activity, which, in turn, recruits E2F1, a key regulator that links cell cycle progression and cell
death, both in vitro and in vivo Cdk2 and E2F1 are key mediators of cisplatin induced apoptosis
in nephrotoxicity.

NEPHROTOXICITY DUE TO RADIOCONTRAST MEDIA
Administration of radio contrast agents causes a decrease in renal medullary oxygenation.
It has also been proposed that the medullary hypoperfusion is caused by constriction of the
descending vasa recta (DVR) due to cytotoxic damage of the endothelial cells of the DVR caused
by RCM.
A decrease in blood flow and hence in oxygen supply may lead to perturbations in the mitochondrial
electron transport chain leading to the production of reactive oxygen species (ROS).
ROS may have a detrimental effect within the cell by oxidizing membrane lipids, inactivating
proteins, oxidizing DNA, and activating cell signaling pathways leading to inflammation and cell
death.

ANALGESIC NEPHROPATHY
● It is injury to the kidney caused by analgesic medications such as aspirin, phenacetin, and
paracetamol. The term usually refers to damage induced by excessive use of combinations
of these medications.
● The specific kidney injuries induced by analgesics are renal papillary necrosis and chronic
interstitial nephritis.
● Aspirin and other NSAIDs are inhibitors of the cyclooxygenases which results in decreased
PGE2 concentration causing a reduction in blood flow.
● The deeper structures of the kidney are most sensitive to decreased blood flow therefore rather
selectively damages the renal papillae, increasing the risk of renal papillary necrosis.

● Amphotericin B binds to sterols in cell membranes, thereby creating pores that compromise
membrane integrity and increase membrane permeability.
● The pathophysiology of nephrotoxicity involves vasoconstriction and direct interaction with
epithelial cell membranes and ultimately causes ischemic injury.
● These alterations are responsible for the decrease in glomerular filtration rate (GFR) and tubular
dysfunction.
● Amphotericin B will decrease renal blood flow.
● Amphotericin B forms pores in membranes that cause tubular dysfunction.
AMPHOTERACIN B NEPHROTOXICITY
● Amphotericin B nephrotoxicity is frequent and severe. Elevated creatinine is associated
with amphotericin B.

CRYSTAL-FORMING DRUG NEPHROTOXICITY
● Crystal-induced AKI most commonly occurs as a result of acute uric acid nephropathy and
following the administration of drugs or toxins that are poorly soluble or have metabolites that are
poorly soluble in urine.
● Crystal-induced acute kidney injury (AKI) is caused by the intratubular precipitation of crystals,
which results in obstruction.
Drugs and toxins cause intratubular crystal-induced obstruction. Common agents include:
●Acyclovir
Birefringent needle-shaped acyclovir crystals can be seen in the urine.
Prevention
Prior hydration urine outputgt75 ml/h
Slow drug infusion for 1-2 hrs
●Sulfonamide antibiotics
Shape: Needle, rosettes ,shock of wheat
Prevention of crystal urea due to sulfonamides:
Alkalinization of the urine to a pH gt 7.15
Sulfadiazine solubility more than 20-fold

REFERENCES:
1. Calcineurin Inhibitor Nephrotoxicity Maarten Naesens,*† Dirk R. J. Kuypers,* and
Minnie Sarwal.
2. Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanisms
and potential approaches to modulation H. Servais Æ A. Ortiz Æ O. Devuyst Æ S. Denamur Æ
P. M. Tulkens Æ M.-P. Mingeot-Leclercq.
3. Molecular Mechanisms of Renal Cellular Nephrotoxicity due to Radiocontrast Media
Ashour Michael,1 Teresa Faga,1 Antonio Pisani,2 Eleonora Riccio,2 Placido Bramanti,3
Massimo Sabbatini,2 Michele Navarra,4 andMichele Andreucci1
4. Aminoglycosides: Nephrotoxicity MARIE-PAULE MINGEOT-LECLERCQ* AND PAUL M.
TULKENS.
5. Cisplatin nephrotoxicity: molecular mechanisms Marie H. Hanigan# and Prasad Devarajan*
6. Nephrotoxicity Mechanisms of Immunosuppressive Drugs Fuad S. Shihab, M.D.
7. The Role of Transport in Chemical Nephrotoxicity* WILLIAM0 . BERNDT
8. Acute nephrotoxicity of NSAID from the fetus to the adult M. MUSU, G. FINCO, R.
ANTONUCCI, E. POLATI, D. SANNA,M. EVANGELISTA, D. RIBUFFO, V. SCHWEIGER, V.
FANOS.
9. http://en.wikipedia.org/wiki/Analgesic_nephropathy
10. Biomarkers for Drug-Induced Renal Damage and Nephrotoxicity—An Overview for Applied
Toxicology,Tobias Christian Fuchs1 and Philip Hewitt1,2
11.http://www.powershow.com/view2b/411251
MWU2O/Nephrotoxic_Drugs_powerpoint_ppt_presentation
12.http://www.powershow.com/view2b/476a83
NWUyN/Drug_induced_nephrotoxicity_powerpoint_ppt_presentation

Molecular mechanism of drug induced nephrotoxicity

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Molecular mechanism of drug induced nephrotoxicity