S.NTypesCharacters

1.Pseudo Renal Failure Increase BUN due to protein catabolism , Normal Cr Eg. Steroids, tetracyclines

2.Interstitial NephritisForm 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.RhabdomyolysisCondition 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 nephropathyDisease 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 injuryElevated in response to gentamicin, mercury, chromium, cadmiumIncreased 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 nucleatedCellsIncreased in diabetic rats and in response to subtotal or unilateral nephrectomyElevated during chromium nephropathyClusterin: In a wide range of tissue expressed secreted glycoproteinInvolved 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-IImediated 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 NEPHROTOXICITYAmphotericin B nephrotoxicity is frequent and severe. Elevated creatinine is associated with amphotericin B.

CRYSTAL-FORMING DRUG NEPHROTOXICITYCrystal-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:AcyclovirBirefringent needle-shaped acyclovir crystals can be seen in the urine.Prevention Prior hydration urine outputgt75 ml/h Slow drug infusion for 1-2 hrsSulfonamide antibioticsShape: Needle, rosettes ,shock of wheatPrevention 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,* andMinnie Sarwal.2. Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanismsand potential approaches to modulation H. Servais A. Ortiz O. Devuyst S. Denamur P. M. Tulkens M.-P. Mingeot-Leclercq.3. Molecular Mechanisms of Renal Cellular Nephrotoxicity due to Radiocontrast MediaAshour Michael,1 Teresa Faga,1 Antonio Pisani,2 Eleonora Riccio,2 Placido Bramanti,3Massimo Sabbatini,2 Michele Navarra,4 andMichele Andreucci14. 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 . BERNDT8. 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_nephropathy10. Biomarkers for Drug-Induced Renal Damage and NephrotoxicityAn Overview for Applied Toxicology,Tobias Christian Fuchs1 and Philip Hewitt1,211.http://www.powershow.com/view2b/411251MWU2O/Nephrotoxic_Drugs_powerpoint_ppt_presentation12.http://www.powershow.com/view2b/476a83 NWUyN/Drug_induced_nephrotoxicity_powerpoint_ppt_presentation

EVALUATION SEMINAR ONMOLECULAR MECHANISMS OF DRUG INDUCED NEPHROTOXICITY.TABLE OF CONTENTS

1. INTRODUCTION2. TYPES OF NEPHROTOXICITY3. BIOMARKERS FOR DRUG INDUCED RENAL DAMAGE4. PATHOGENIC MECHANISM5. NEPHROTOXICITY DUE TO a) Aminoglycosidesb) Cyclophosphamidec) Cisplatind) Radiocontraste) Analgesicf) Amphotericing) Crystal forming drug6. REFERNCENEPHROTOXICITYINTRODUCTION: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. Assessment of NephrotoxicityUrinalysis: Volume, pH, Glucose, Proteins, Cells

Blood chemistry: Blood urea nitrogen, Creatinine

Histopathology

Pathophysiologic ResponsesAcute renal failure

Decline in GFR

Azotemia

Chronic renal failure

Adaptive responses

Compensatory increase in single nephron GFR

Metallothionein induction

Stress protein induction