24/10/1436 Drug induced nephrotoxicity Naser Hadavand

Definitions Type Onset Severity Classification of Drug Induced Disordres

Definition and Classifications of Adverse Reaction Terms Adverse Event: Adverse Drug Reaction: Side Effect:

Definition and Classifications of Adverse Reaction Terms Adverse Event: Any untoward medical occurrence that may present during treatment with pharmaceutical product but which does not necessarily have a causal relationship with treatment.

Definition and Classifications of Adverse Reaction Terms Adverse Event: Any untoward medical occurrence that may present during treatment with pharmaceutical product but which does not necessarily have a causal relationship with treatment. Adverse Drug Reaction: A response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function.

Definition and Classifications of Adverse Reaction Terms Adverse Event: Any untoward medical occurrence that may present during treatment with pharmaceutical product but which does not necessarily have a causal relationship with treatment. Adverse Drug Reaction: A response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function. Side Effect: Any unintended effect of a pharmaceutical product occurring at doses normally used in man which is related to the pharmacological properties of drug.

Examples Adverse Event: Adverse Drug Reaction: Side Effect:

Adverse Drug Reaction vs. Adverse Event Adverse Drug Reaction (event attributed to drug) Adverse Event All Spontaneous reports Events not attributed to drug Diseases Other Drugs Environment Diet Genetics Compliance Other factors

Definitions Type Onset Severity Classification

Comparison Type A and Type B

Adverse Drug Reactions Unwanted effects of drugs are separated into those represent: 1. Augmented pharmacological effects of a substance but qualitatively normal (Type A) 2. Qualitatively bizarre pharmacological effects (Type B) 3. Long term effects (Type C) 4. Delayed effects (Type D) 5. End of use (Type E) 6. Failure (Type F) * Most long term effects are Type A reactions.

Introduction Occurs frequently in patients treated with diagnostic and therapeutic agents Manifestation Decrease in renal function(often reversible) Is seen in which patients? Drug induced nephrotoxicity

Incidence 5% . 25% . 8% . 7% .

Incidence Frequent adverse event in hospitalized patients - 7% of all drugs toxicity - 1/5 of all ARF induced by drugs Mortality: 8% Drugs induced nephrotoxicity in general: Aminoglycosides, Cisplatin, Radiographic contrast media Drugs induced ARF: AG, Pentamidine,Cephalosporins, NSAIDs, ACEIs, Diuretics(29%)

Risk factors: Idiosyncratic Direct cumulative toxicity No generalizable risk factors are applicable to all drug classes and patient situation,Exception: ARF due to NSAIDs & ACEIs The risk factors are: Preexisting renal insufficiency & decrease effective renal blood flow from volume depletion and HF, liver dx.

Recognition and assessment of renal toxicity: Hospitalized patients: 1-recognized quickly 2-by lab test: BUN,Cr 3-decrease in urine out put(ACEIs,NSAIDs, Radiographic contrast) Out patients recognized by advanced renal dysfunction Signs

Classification of drug induced renal disease: Based on mechanism of toxicity Presenting of renal manifestations: CRF,ARF,Pyuria,Hematuria, Proteinuria Therapeutic use and the various types of nephropathies they may produced Renal structural and functional alterations(produced by drugs)

Definitions: Pseudo Renal Failure Interstitial Nephritis Acute interstitial nephritis Chronic interstitial nephritis Acute Glomerulonephritis Acute Tubular Necrosis Crystal nephropathy Rhabdomyolysis Nephrotic Syndrome minimal-change nephropathy

Pseudo Renal Failure (Normal GFR) BUN due to protein catabolism, Normal Cr Steroids, tetracyclines SCr due to competitive inhibition of creatinine secretion, Normal BUN Trimethoprim, Cimetidine, Triamterene - 15-35% rise SCr fully expressed after 3 days - More sig in pts with pre-existing renal dysfunction - Can occur with normal doses - Completely reversible when drug is discontinued (J Int Med 1999l246:247-52; TDM 1987;9:161-5)

Definitions: Interstitial Nephritis Interstitial nephritis (or Tubulo-interstitial nephritis) is a form of nephritis affecting the interstitium of the kidneys surrounding the tubules. This disease can be either acute, meaning it occurs suddenly, or chronic, meaning it is ongoing and eventually ends in kidney failure.nephritisinterstitium kidneystubules

Definitions: Interstitial Nephritis When caused by an allergic reaction, the symptoms of acute tubulointerstitial nephritis are: - fever (27% of patients) - rash (15% of patients) - enlarged kidneys. Other: Dysuria, and lower back pain.ysuria In chronic tubulointerstitial nephritis: nausea, vomiting, fatigue, and weight loss. hyperkalemia, metabolic acidosis, and kidney failure.hyperkalemiametabolic acidosis Blood tests: Eosinophilia, Cr & BUN Urinary findings: Eosinophiluria, Isosthenuria, hematuria, Sterile pyuria: white blood cells and no bacteriaEosinophiluriaIsosthenuriamaturia pyuria

Acute interstitial nephritis Symptoms and Signs u Classic triad (Methicillin induced hypersensitivity)Methicillin Low grade fever (>70% of cases) Rash (>30% of cases) Arthralgia (>15% of cases) u Acute Renal Failure Acute Renal Failure Oliguria Malaise Nausea or Vomiting NauseaVomiting Labs: General u Urinalysis Urinalysis Eosinophiluria Eosinophil Proteinuria Proteinuria Fractional Excretion of Sodium >1% Fractional Excretion of Sodium u Renal Function tests with renal insufficiency Renal Function Cr & BUN increased u Miscellaneous Hyperchloremic Metabolic AcidosisMetabolic Acidosis

Acute interstitial nephritis Causes u Infection Diphtheria, Group A beta hemolytic Streptococcus (classic) DiphtheriaStreptococcus Legionella, Yersinia, Staphylococcus or Streptococcus infection LegionellaYersiniaStaphylococcusStreptococcus Mycobacterium, Toxoplasmosis, Mycoplasma, Leptospira MycobacteriumToxoplasmosisMycoplasmaLeptospira Rickettsia, Syphilis, Herpes viruses (e.g. CMV, EBV, HSV) RickettsiaSyphilis Human Immunodeficiency Virus (HIV),Hantavirus Human Immunodeficiency VirusHantavirus Hepatitis C, Mumps Hepatitis CMumps u Medications (AIN occurs >2 weeks after drug started) Penicillins and Cephalosporins PenicillinCephalosporin Hypersensitivity (fever, rash, arthralgia) Sulfonamides Sulfonamide Vasculitis reaction Vasculitis NSAIDs NSAID Nephrotic Syndrome type reaction Nephrotic Syndrome Rifampin, Diuretics (Thiazides and Lasix), Allopurinol, Cimetidine, Ciprofloxacin RifampinDiureticLasixAllopurinolCimetidineCiprofloxacin Dilantin Dilantin Other medications have caused AIN to a lesser extent u Miscellaneous conditions Glomerulonephritis, Necrotizing Vasculitis, Systemic Lupus Erythematosus GlomerulonephritisVasculitisSystemic Lupus Erythematosus Acute kidney transplant rejection Symptoms and Signs u Classic triad (Methicillin induced hypersensitivity)Methicillin Low grade fever (>70% of cases) Rash (>30% of cases) Arthralgia (>15% of cases) u Acute Renal Failure Acute Renal Failure Oliguria Malaise Nausea or Vomiting NauseaVomiting Labs: General u Urinalysis Urinalysis Eosinophiluria Eosinophil Proteinuria Proteinuria Fractional Excretion of Sodium >1% Fractional Excretion of Sodium u Renal Function tests with renal insufficiency Renal Function Serum Creatinine increased Serum Creatinine Blood Urea Nitrogen increased Blood Urea Nitrogen u Miscellaneous Hyperchloremic Metabolic AcidosisMetabolic Acidosis

Definitions: Acute Glomerulonephritis Glomerulonephritis, also known as glomerular nephritis, abbreviated GN, is a renal disease (usually of both kidneys) characterized by inflammation of the glomeruli, or small blood vessels in the kidneys.renalinflammationglomeruli It may present with isolated hematuria and/or proteinuria (blood or protein in the urine); or as a nephrotic syndrome, a nephritic syndrome, acute renal failure, or chronic renal failure.hematuriaproteinuriaurinenephrotic syndromenephritic syndromerenal failure Primary causes are intrinsic to the kidney. Secondary causes are associated with certain infections (bacterial, viral or parasitic pathogens), drugs, systemic disorders (SLE, vasculitis), or diabetes.SLE

Definitions: Acute Tubular Necrosis Acute tubular necrosis (ATN) is a medical condition involving the death of tubular cells that form the tubule that transports urine to the ureters while reabsorbing 99% of the water (and highly concentrating the salts and metabolic byproducts). Tubular cells continually replace themselves and if the cause of ATN is removed then recovery is likely. ATN presents with acute kidney injury (AKI) and is one of the most common causes of AKI. The presence of "muddy brown casts" of epithelial cells found in the urine during urinalysis is pathognomonic for ATN.tubuleurineuretersacute kidney injuryurinalysis

Definitions: Crystal nephropathy Several medications that are insoluble in human urine are known to precipitate within the renal tubules. Intratubular precipitation of either exogenously administered medications or endogenous crystals (induced by certain drugs) can promote chronic and acute kidney injury, termed crystal nephropathy. Clinical settings that enhance the risk of drug or endogenous crystal precipitation within the kidney tubules include: - true or effective intravascular volume depletion - underlying kidney disease - and certain metabolic disturbances that promote changes in urinary pH favoring crystal precipitation.

Definitions: Rhabdomyolysis Rhabdomyolysis is a condition in which damaged skeletal muscle tissue, breaks down rapidly. 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. The severity of the symptoms, which may include muscle pains, vomiting and confusion, depends on the extent of muscle damage and whether kidney failure develops.skeletal musclemuscle cellsmyoglobinkidneyskidney failuremuscle painsvomitingconfusion The muscle damage may be caused by physical factors (e.g. crush injury, strenuous exercise), medications, drug abuse, and infections. Some people have a hereditary muscle condition that increases the risk of rhabdomyolysis.crush injury medicationsdrug abuseinfections The diagnosis is usually made with blood tests and urinalysis. The mainstay of treatment is generous quantities of intravenous fluids, but may include dialysis or hemofiltration in more severe cases.blood testsurinalysisintravenousdialysishemofiltration Rhabdomyolysis and its complications are significant problems for those injured in disasters such as earthquakes and bombings. Relief efforts in areas struck by earthquakes often include medical teams with the skills and equipment to treat survivors with rhabdomyolysis. The disease was first described in the 20th century, and important discoveries as to its mechanism were made during the Blitz of London in 1941. Horses may also suffer from rhabdomyolysis from a variety of causes.the Blitz of LondonHorses

Definitions: Nephrotic Syndrome Nephrotic syndrome is a nonspecific kidney disorder characterised by a number of diseases: proteinuria, hypoalbuminemia and edema.kidneydiseasesproteinuriahypoalbuminemiaedema It is characterized by an increase in permeability of the capillary walls of the glomerulus leading to the presence of: glomerulus - high levels of protein passing from the blood into the urine (proteinuria at least 3.5 grams per day per 1.73m 2 body surface area);proteinbloodurineproteinuria - low levels of protein in the blood (hypoproteinemia or hypoalbuminemia),hypoproteinemiahypoalbuminemia - Ascites and edemaedema - High cholesterol (hyperlipidaemia or hyperlipemia)cholesterolhyperlipidaemiahyperlipemia - Predisposition for coagulation.coagulation Kidneys affected by nephrotic syndrome have small pores in the podocytes, large enough to permit proteinuria (and subsequently hypoalbuminemia,

Diagnosis: Proteinuria: >3.5g/d Hypoalbuminemia: SAlb

Definitions: minimal-change nephropathy Minimal Change Disease (also known as Nil Lesions or Nil Disease (lipoid nephrosis)) is a disease of the kidney that causes nephrotic syndrome and usually affects children (peak incidence at 23 years of age).kidneynephrotic syndrome People with one or more autoimmune disorders are at increased risk of developing minimal change disease. Having minimal change disease also increases the chances of developing other autoimmune disorders. Most cases of MCD are idiopathic, however there have been causes of secondary MCD identified, including medications, immunizations, neoplasm, and infection. Case reports and literature reviews have shown an association between MCD and malignancies, particularly hematologic malignancies, such as Hodgkins disease, non-Hodgkin lymphomas, or leukemias. Colorectal cancer-associated MCD is uncommon and has been reported in only a few cases to date.

CLASSIFICATIONS Anuric: < 50ml/day urine output Oliguric: 50-400ml/day urine output Non-oliguric: >400ml/day urine output

Urine Analysis Urinalysis (complete) (urine) Appearance: clear, yellow. Specific gravity: 1.001 - 1.035 pH: 4.6 - 8.0 Protein: negative Glucose: negative Ketones: negative Bilirubin: negative Occult blood: negative WBC esterase: negative Nitrite: negative WBC:

Kidney Function Tests Urea Nitrogen blood (BUN) (serum) 7 - 30 mg/dL Alternative source: 8-25 mg/dL 2.5 - 10.7 mmol urea /L Alternative source: 2.9-8.9 mmol/L Creatinine (Serum)0.7 - 1.4 mg/dl (

Pre Renal: BUN/ Cr >20 Post Renal: BUN/ Cr 10 20 Renal: BUN/ Cr < 10

Kidney Function Tests PaCO2: Normal: 35 - 45 mmHg (4.6 - 6 kPa) Respiratory acidosis: > 45 mmHg (> 6 kPa) Respiratory alkalosis: +2 mmol/L Severe> +13 Marked9 to 13 Moderate6 to 9 Mild 4 to 6 [Base excess (BE) is the mmol/L of base that needs to be removed to bring the pH back to normal when PCO2 is corrected to 5.3 kPa or 40 mmHg. During the calculation any change in pH due to the PCO2 of the sample is eliminated, therefore, the base excess reflects only the metabolic component of any disturbance of acid base balance.]

Anion gap = Na+ - [CL- + HCO3-] Difference between calculated serum anions and cations. Based on the principle of electrical neutrality, the serum concentration of cations (positive ions) should equal the serum concentration of anions (negative ions). However, serum Na+ ion concentration is higher than the sum of serum Cl- and HCO3- concentration. Na+ = CL- + HCO3- + unmeasured anions (gap). Normal anion gap: 12 mmol/L (10 - 14 mmol/L)

ESTIMATION OF RENAL FUNCTION Cockcroft and Gault Equation: Estimates renal function when creatinine levels are at steady-state u not usually the case in acute renal failure CL Cr (ml/min) = (140-Age)(Wt.) 72(Scr) = 0.85 (female)

Serum Creatinine Creatinine 1.0 mg/dL Normal GFR Creatinine 2.0 mg/dL 50% reduction in GFR Creatinine 4.0 mg/dL 7085% reduction in GFR Creatinine 8.0 mg/dL 9095% reduction in GFR

Estimate Creatinine Clearance: (ml/min) Cockcroft and Gault equation: CrCl: (140 - age) x IBW / (Scr x 72) (x 0.85 for females) Note: if the ABW (actual body weight) is less than the IBW use the actual body weight for calculating the CRCL. If the patient is >65yo and creatinine

Normal Blood Gases ArterialVenous pH7.35 - 7.457.32 - 7.42 Not a gas, but a measurement of acidity or alkalinity, based on the hydrogen (H+) ions present. The pH of a solution is equal to the negative log of the hydrogen ion concentration in that solution: pH = - log [H+]. PaO280 to 100 mm Hg.28 - 48 mm Hg The partial pressure of oxygen that is dissolved in arterial blood. New Born Acceptable range 40-70 mm Hg. Elderly: Subtract 1 mm Hg from the minimal 80 mm Hg level for every year over 60 years of age: 80 - (age- 60) (Note: up to age 90) HCO3 22 to 26 mEq/liter (2128 mEq/L) 19 to 25 mEq/liter The calculated value of the amount of bicarbonate in the bloodstream. Not a blood gas but the anion of carbonic acid. PaCO235-45 mm Hg38-52 mm Hg The amount of carbon dioxide dissolved in arterial blood. Measured. Partial pressure of arterial CO2. (Note: Large A= alveolor CO2). CO2 is called a volatile acid because it can combine reversibly with H2O to yield a strongly acidic H+ ion and a weak basic bicarbonate ion (HCO3 -) according to the following equation: CO2 + H2O H + + HCO3 B.E. 2 to +2 mEq/liter Other sources: normal reference range is between -5 to +3. The base excess indicates the amount of excess or insufficient level of bicarbonate in the system. (A negative base excess indicates a base deficit in the blood.) A negative base excess is equivalent to an acid excess. A value outside of the normal range (-2 to +2 mEq) suggests a metabolic cause for the abnormality. Calculated value. The base excess is defined as the amount of H+ ions that would be required to return the pH of the blood to 7.35 if the pCO2 were adjusted to normal. It can be estimated by the equation: Base excess = 0.93 (HCO3 - 24.4 + 14.8(pH - 7.4)) Alternatively: Base excess = 0.93HCO3 + 13.77pH - 124.58 A base excess > +3 = metabolic alkalosis a base excess < -3 = metabolic acidosis SaO295% to 100%50 - 70% The arterial oxygen saturation.

Definitions Type Onset Severity

NSAIDs

Acute interstitial nephritis Acute Tubular Necrosis Obstructive

Aminoglycosides Is once daily dosing less nephrotoxic compared to traditional dosing?

Amphotericin B Are Liposomal formulations affect nephrotoxicity

- NSAIDs - Cyclosporine - Amphotericin-B - Radiocontrast Media - Vasopressors

A. Tubular cell toxicity ACE inhibitors B. Altered intraglomerular hemodynamics ARBs C. Crystal nephropathy Antivirals D. Rhabdomyolysis Statins

u Relative Serum Creatinine increase 50% over baselineSerum Creatinine u Absolute Serum Creatinine increaseSerum Creatinine Serum Creatinine baseline 2 mg/dl: Creatinine increase 1.0 mg/dl over baseline Serum CreatinineCreatinine

Drug-Induced Acute Renal Dysfunction Pseudo Renal Failure Acute Renal Failure - Prerenal NSAIDs, CyA/Tacrolimus, ACEI/ARB, Diuretics - Intrinsic ATN vs AIN ATN Aminoglycosides, Amphotericin B, Radiocontrast Media - Obstructive Methotrexate, Acyclovir, Indinavir, Rhabdomyolysis (Statins)

DRUG-INDUCED RENAL FAILURE

ETIOLOGY: pre-renal u Decreased cardiac output: CHF,MI,PE, Beta-blockers u Peripheral vasodilation: bacterial sepsis, vasodilators (nitrates, hydralazine,etc.) u Hypovolemia: blood loss,Severe dehydration, diarrhea, burns, third-spacing, diuresis(diuretics) u Vascular Obstruction: NSAIDS, ACE-I, Vasopressors, renal artery occlusion

u (NSAIDs) u u u

History 1 The first reference to aspirin was by a 5 th century BC Greek physician who rote of a bitter powder that came from the bark of the willow tree, and it eased pains and reduced fever. The medicinal part of the plant is the inner bark of the tree. The active extract of the bark is called salicin after the Latin name for the white willow tree. It was isolated in crystalline form in 1828 by Henri Leroux, a French pharmacist. Raffaele Piria, an Italian chemist was able to convert it to salicylic acid. Salicylic acid was isolated from the herb called meadowsweet by German researchers in 1839. While it was somewhat effective, it also caused digestive problems when consumed in high doses. A French chemist, Charles Frederic Gerhardt, first prepared acetylsalicylic acid in 1853 (named aspirin in 1899). This preparation of aspirin was one of many reactions Gerhardt conducted for his paper on anhydrides and he did nothing further with it. Six years later in 1859, von Gilm created the substance again. In 1897, a chemist at Friedrich Bayer and Co. began investigating acetylsalicylic acid as a less-irritating replacement for the commonly used salicylate medicines. By 1899 Bayer was marketing it world wide. obtained acetylsalicylic acid and claimed to discover aspirin. Regardless of that, aspirin was finally manufactured and put on the market to help those in pain or with fever.

History 2 Sodium salicylate, discovered in 1763, was the first NSAID. Gastrointestinal toxicity (particularly dyspepsia) associated with the use of acetylsalicylic acid (ASA) led to the introduction of phenylbutazone, an indoleacetic acid derivative, in the early 1950s; this was the first non-salicylate NSAID developed for use in patients with inflammatory conditions. Phenylbutazone is a weak prostaglandin synthetase inhibitor that also induces uricosuria. It was shown to be a useful agent in patients with ankylosing spondylitis and gout. Concerns related to bone marrow toxicity, particularly in women over the age of 60, have essentially eliminated the use of this drug. Indomethacin was developed in the 1960s as a substitute for phenylbutazone. The following years witnessed the development of more and more NSAIDs in an effort to enhance patient compliance (by decreasing the absolute number of pills and frequency with which they are taken each day), reduce toxicity, and increase the antiinflammatory effect.

History 3 Salicylates were discovered in the mid-19th century There were two periods of NSAID drug discovery post-World War 2, the period up to the 1970's which was the pre-prostaglandin period and thereafter up to the latter part of the last century in which their effects on prostaglandin production formed part of the screening in the drug-discovery process. Those drugs developed up to the 1980-late 90's were largely discovered empirically following screening for anti-inflammatory, analgesic and antipyretic activities in laboratory animal models. Some were successfully developed that showed low incidence of gastro-intestinal (GI) side effects (the principal adverse reaction seen with NSAIDs) than seen with their predecessors (e.g. aspirin, indomethacin, phenylbutazone); the GI reactions being detected and screened out in animal assays.

History 3 In the 1990's an important discovery was made from elegant molecular and cellular biological studies that there are two cyclooxygenase (COX) enzyme systems controlling the production of prostanoids [prostaglandins (PGs) and thromboxane (TxA2)]; COX-1 that produces PGs and TxA2 that regulate gastrointestinal, renal, vascular and other physiological functions, and COX-2 that regulates production of PGs involved in inflammation, pain and fever. The stage was set in the 1990's for the discovery and development of drugs to selectively control COX-2 and spare the COX-1 that is central to physiological processes whose inhibition was considered a major factor in development of adverse reactions, including those in the GI tract. At the turn of this century, there was enormous commercial development following the introduction of two new highly selective COX-2 inhibitors, known as coxibs (celecoxib and rofecoxib) which were claimed to have low GI side effects.

History 4 While found to have fulfilled these aims in part, an alarming turn of events took place in the late 2004 period when rofecoxib was withdrawn worldwide because of serious cardiovascular events and other coxibs were subsequently suspected to have this adverse reaction, although to a varying degree. Major efforts are currently underway to discover why cardiovascular reactions took place with coxibs, identify safer coxibs, as well as elucidate the roles of COX-2 and COX-1 in cardiovascular diseases and stroke in the hope that there may be some basis for developing newer agents (e.g. nitric oxide-donating NSAIDs) to control these conditions. Moreover, new anti-inflammatory drugs are being discovered and developed based on their effects on signal transduction and as anti-cytokine agents and these drugs are now being heralded as the new therapies to control those diseases where cytokines and other nonprostaglandin components of chronic inflammatory and neurodegenerative diseases are manifest.

AspirinCelecoxib DiclofenacIndomethacin IbuprofenKetorolac Mefenamic acidNaproxen SulindacSalicylic acid PiroxicamTolmetin Sodium salicylateIndomethacin Naproxen

Endothelium, brain, spinal cord Kidney (Macula densa), ovaries, uterus N.B.: COX-2 also in + GCS Classical NSAIDs

Mechanism of action Prostaglandins act (among other things) as messenger molecules in the process of inflammation. This mechanism of action was elucidated by John Vane (19272004), who received a Nobel Prize for his work (see Mechanism of action of aspirin).inflammationmechanism of actionJohn VaneNobel PrizeMechanism of action of aspirin Acetaminophen is not considered an NSAID because it has little anti- inflammatory activity. It treats pain mainly by blocking COX-2 mostly in the central nervous system, but not much in the rest of the body. Acetaminophen The COX-3 pathway was believed to fill some of this gap but recent findings make it appear unlikely that it plays any significant role in humans and alternative explanation models are proposed.COX-3 NSAIDs are also used in the acute pain caused by gout because they inhibit urate crystal phagocytosis besides inhibition of prostaglandin synthase.gouturatephagocytosis

Mechanism of action Antipyretic activity NSAIDS have antipyretic activity and can be used to treat fever. Fever is caused by elevated levels of prostaglandin E2, which alters the firing rate of neurons within the hypothalamus that control thermoregulation. NSAIDSantipyreticprostaglandin E2hypothalamus Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus.prostanoidPGE2 hypothalamus PGE2 signals to the hypothalamus to increase the body's thermal set point. Ibuprofen has been shown more effective as an antipyretic than acetaminophen (paracetamol).Ibuprofenantipyretic acetaminophen Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D & E.Arachidonic acid

Pharmacokinetics: - Most NSAIDs are absorbed completely - Have negligible first-pass hepatic metabolism - Tightly bound to serum proteins - Have small volumes of distribution - Half-lives of the NSAIDs vary but in general can be divided into : "short-acting" (less than six hours, including ibuprofen, diclofenac, ketoprofen and indomethacin) and "long-acting" (more than six hours, including naproxen, celecoxib, meloxicam, nabumetone and piroxicam). Patients with hypoalbuminemia (due, for example, to cirrhosis or active rheumatoid arthritis) may have a higher free serum concentration of the drug.

Drug interactions NSAIDs reduce renal blood flow and thereby decrease the efficacy of diuretics,diuretics

Drug interactions NSAIDs reduce renal blood flow and thereby decrease the efficacy of diuretics, and inhibit the elimination of lithium and methotrexate.diureticslithiummethotrexate NSAIDs cause hypocoagulability, which may be serious when combined with other drugs that also decrease blood clotting, such as warfarin.hypocoagulabilitywarfarin NSAIDs may aggravate hypertension (high blood pressure) and thereby antagonize the effect of antihypertensives, such as ACE Inhibitors.hypertension antihypertensivesACE Inhibitors NSAIDs may interfere and reduce efficiency of SSRI antidepressantsSSRI

Indications NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present. Research continues into their potential for prevention of colorectal cancer, and treatment of other conditions, such as cancer and cardiovascular disease.paincolorectal cancercardiovascular disease NSAIDs are generally indicated for the symptomatic relief of the following conditions: Rheumatoid arthritis Osteoarthritis Rheumatoid arthritisOsteoarthritis Inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome)ankylosing spondylitispsoriatic arthritis Reiter's syndrome Acute gout Dysmenorrhoea (menstrual pain)goutDysmenorrhoeamenstrual Metastatic bone pain Headache and migraine MetastaticHeadachemigraine Postoperative pain Mild-to-moderate pain due to inflammation and tissue injury Muscle stiffness and pain due to Parkinson's diseaseParkinson's disease Pyrexia (fever) Ileus Renal colic PyrexiafeverIleusRenal colic Ductus arteriosus is not closed within 24 hours of birth Ductus arteriosus Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for inhibition of platelet aggregation. This is useful in the management of arterial thrombosis and prevention of adverse cardiovascular events. Aspirin inhibits platelet aggregation by inhibiting the action of thromboxane A 2. AspirinCOX-1platelet thrombosisthromboxane A 2

NSAIDs - Common Adverse Effects Platelet Dysfunction Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects) Acute Renal Failure in susceptible Sodium+ water retention and edema Analgesic nephropathy Prolongation of gestation and inhibition of labor. Hypersenstivity (not immunologic but due to PG inhibition) GIT bleeding and perforation

NSAIDs u 10-1% u NSAIDs ( ) ACE ( ) u

NSAIDs/COXibs 5% NSAIDs . .

NSAIDs/COXibs Use with caution in CKD (grade 3 or greater) Inhibit renal vasodilatory prostaglandins E2 & I2 Produced by COX-2 Reversible reduction in GFR Higher risk if intravascular volume depletion Management: D/C drug, use alternate analgesia Hypertension Edema, sodium and water retention Mean increase SBP 5 mm Hg Hyperkalemia Risk blunting of PG-mediated renin release

NSAIDs

Sulindac Naproxen

Analgesic nephropathy Analgesic nephropathy involves damage to one or both kidneys caused by overexposure to mixtures of medications, especially over-the-counter pain remedies (analgesics). - Injuries: renal papillary necrosis and chronic interstitial nephritis.renal papillary necrosischronic interstitial nephritis - Result: decreased blood flow to the kidney, rapid consumption of antioxidants, andblood flow to the kidneyantioxidants subsequent oxidative damage to the kidney. This kidney damage mayoxidative damage lead to progressive chronic renal failure, abnormal urinalysis results,chronic renal failureurinalysis high blood pressure high blood pressure, and anemia.anemia

Analgesic nephropathy Causes, incidence, and risk factors - Analgesic nephropathy involves damage within the internal structures of the kidney. It is caused by long-term use of analgesics, especially over-the-counter (OTC) medications that contain phenacetin or acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin or ibuprofen.analgesicsacetaminophenaspirinibuprofen - About 6 or more pills per day for 3 years increases the risk some for this problem. This frequently occurs as a result of self-medicating, often for some type of chronic pain. - Analgesic nephropathy occurs in about 4 out of 100,000 people, mostly women over 30. The rate has decreased significantly since phenacetin is no longer widely available in OTC preparations.

Analgesic nephropathy Risk factors include: - Use of OTC analgesics containing more than one active ingredient - Chronic headaches, painful menstrual periods, backache, or musculoskeletal pain - History of dependent behaviors including smoking, alcoholism, and excessive use of tranquilizers

Analgesic nephropathy Symptoms There may be no symptoms. Symptoms of chronic kidney disease are often present over time and may include:chronic kidney disease Weakness, Fatigue WeaknessFatigue Increased urinary frequency or urgency Increased urinary frequency or urgency Blood in the urine Blood in the urine Flank pain or back pain Flank pain Decreased urine output Decreased urine output Decreased alertness : Drowsiness, Confusion, delirium, Lethargy Decreased alertness DrowsinessConfusiondeliriumLethargy Decreased sensation, numbness (especially in the legs) Decreased sensationnumbness Nausea, vomiting Nauseavomiting Easy bruising or bleedingbruisingbleeding Swelling, generalized Swelling

Analgesic nephropathy Signs and tests A physical examination may show signs of interstitial nephritis or kidney failure.interstitial nephritiskidney failure. Blood pressure may be high abnormal heart or lung sounds There may be signs of premature skin aging Lab tests may show blood and pus in the urine, with or without signs of infection There may be mild or no loss of protein in the urine.protein in the urine Tests that may be done include: - CBC - sedimentation in the urine - Intravenous pyelogram(IVP) - Toxicology screen - Urinalysis

Analgesic nephropathy Treatment The primary goals of treatment are to prevent further damage and to treat any existing kidney failure. Stop taking all suspect painkillers, particularly OTC medications. Signs of kidney failure should be treated as appropriate. This may include diet changes, fluid restriction, dialysis or kidney transplant, or other treatments.kidney transplant Counseling, behavioral modification, or similar interventions may help you develop alternative methods of controlling chronic pain. Expectations (prognosis) The damage to the kidney may be acute and temporary, or chronic and long term.

Analgesic nephropathy Complications Acute renal failure Acute renal failure Chronic renal failure Chronic renal failure Interstitial nephritis Interstitial nephritis Renal papillary necrosis (tissue death) Renal papillary necrosis Urinary tract infections, chronic or recurrent Urinary tract infectionschronic Hypertension Hypertension Transitional cell carcinoma of the kidney or uretercarcinoma

Drug-Induced Acute Renal Dysfunction Acute Renal Failure - Prerenal NSAIDs, CyA/Tacrolimus, ACEI/ARB, Diuretics

Cyclosporine, Tacrolimus Can cause: - pre-renal (hemodynamically mediated) - chronic interstitial nephritis Pre-renal dose-related preglomerular arteriolar vasoconstriction or direct proximal tubule damage SCr ~ 30% More common in first 6 mos of therapy Hypertension, K, Mg may occur Reversible with lowering dose (caution rejection) Monitor blood levels Renal biopsy to distinguish acute CyA nephrotoxcity from allograft rejection

BUN/Cr Angiography Biopsy

Side Effects

Putting Guidelines into Practice ACE INHIBITORS ACE Inhibitors In Whom and When? Indications: Potentially all patients with heart failure First-line treatment (along with beta-blockers) in NYHA class IIV heart failure Contra-indications: History of angioneurotic oedema Cautions/seek specialist advice: Significant renal dysfunction (creatinine >2.5 mg/dL or 221 mol/L) or hyperkalaemia (K + >5.0 mmol/L) Symptomatic or severe asymptomatic hypotension (SBP

Drug induced renal structural functional alteration Psuedo renal failure Hemodynamically mediated renal failure Renal vascular alterations Glomerular alteration Acute tubular necrosis Tubulointerstitial disease Obstructive nephropathy Nephrolithiasis Increase in BUN and Cr without a decrease in GFR Increase in BUN and Cr=norm Corticosteroid,TC(these increase protein catabolism Increase in Cr,BUN=norm TMP,Pyrimethamine,Cimetidine Reduction glumerular capillary hydrostatic pressure Inhibition of prostaglandin- dependant renal blood flow Nonspecific renal vasocons Increase vascular permeability Increase in colloid oncotic pressure

Afferent Arteriolar vasoconstrictors Vasodilatory Prostaglandin Inhibitors - NSAIDs - COX-2 Inhibitors Direct Afferent Arteriolar Vasoconstrictors - Cyclosporine - Amphotericin-B - Radiocontrast Media - Vasopressors

Efferent Arteriolar vasodilators Renin-Angiotensin-Aldosterone - ACEIs - ARBs Direct Efferent Arteriolar Vasodilators - CCBs dihydropyridine: Diltiazem, Verapamil

Acute Renal Failure: PRE-RENAL ACEI/ARB NSAIDs Diuretics Immunosuppressives (CyA, Tacrolimus)

Acute Renal Failure: PRE-RENAL ACEI/ARB At the start of the treatment a decrease of urine volume and increase of creatinine by 30% indicates Damage is reversible Rehydration of patient is advisable Initiate treatment with short acting (captopril) and titrate later with long acting

ACE Inhibitors & ARBs Uremia, hyper K, dialysis dependence Cr > 3.5 consult nephrology! Avoid in bilat renal artery stenosis - ARB causes less renal failure than ACE Inhibitor Strategy: u BP, K, Cr u diuretic holiday x days before start u start captopril 1 st, then long-acting u Ramipril: CrCl < 40, give 25% of normal dose u Losartan: avoid if GFR < 30

Risk Factors for ARF with ACEI/ARB Decreased intravascular volume (dehydration, diuretic overuse, poor fluid intake, CHF, vomiting, diarrhea) Use of afferent vasoconstrictor agents (NSAIDs, cyclosporine, tacrolimus) Sepsis Renal-artery stenosis Polycystic kidney disease

Putting Guidelines into Practice ACE INHIBITORS ACE Inhibitors How to Use Start with a low dose Double dose at not less than two weekly intervals Aim for target dose or, failing that, the highest tolerated dose Remember some ACE inhibitor is better than no ACE inhibitor Monitor blood chemistry (urea, creatinine, K + ) and blood pressure When to stop up-titration/down-titration see PROBLEM SOLVING

Putting Guidelines into Practice ACE INHIBITORS ACE Inhibitors Problem Solving (continued) Worsening renal function: Some increase in urea (blood urea nitrogen), creatinine and K + is to be expected after initiation; if the increase is small and asymptomatic no action is necessary An increase in creatinine of up to 50% above baseline, or 3 mg/dL (266 mol/L), whichever is the smaller, is acceptable An increase in K + 6.0 mmol/L is acceptable If urea, creatinine or K + rise excessively, consider stopping concomitant nephrotoxic drugs (e.g. NSAIDs), other K + supplements/ K + retaining agents (triamterene, amiloride) and, if no signs of congestion, reducing the dose of diuretic If greater rises in creatinine or K + than those outlined above persist, despite adjustment of concomitant medications, halve the dose of ACE inhibitor and recheck blood chemistry; if there is still an unsatisfactory response, specialist advice should be sought

Putting Guidelines into Practice ACE INHIBITORS ACE Inhibitors Problem Solving (continued) Worsening renal function (cont.): If K + rises to >6.0 mmol/L, or creatinine increases by >100% or to above 4 mg/dL (354 mol/L), the dose of ACE inhibitor should be stopped and specialist advice sought Blood chemistry should be monitored serially until K + and creatinine have plateaued NOTE: it is very rarely necessary to stop an ACE inhibitor and clinical deterioration is likely if treatment is withdrawn; ideally, specialist advice should be sought before treatment discontinuation

ACE-Inhibitors A limited increase in serum creatinine of as much as 35% above baseline with ACE inhibitors or ARBs is acceptable and not a reason to withhold treatment unless hyperkalemia develops. an increase in SCr level, if it occurs, will happen within the first 2 weeks of therapy initiation. JNC-7

ACEIs - Additional Considerations Compelling indications : DM, HF, post-MI, high risk CAD, chronic kidney disease, recurrent stroke prevention (6 of 7)Compelling indications : DM, HF, post-MI, high risk CAD, chronic kidney disease, recurrent stroke prevention (6 of 7) May have unfavorable effects on: hyperkalemiaMay have unfavorable effects on: hyperkalemia Contraindicated in pregnancy Contraindicated in pregnancy

Receptors Angiotensin Receptor Blocker: Mechanism of Action AT II Receptor Blocker Antiproliferative Action Vasodilation Proliferative Action Vasoconstriction ATIIATI Angiotensinogen Other Pathways Renin AT I Receptor Blocker Angiotensin I Angiotensin II ACE

Angiotensin II Receptor Antagonists Candesartan (Atacand) Eprosartan (Tevetan) Irbesartan (Avapro) Losartan (Cozaar) Olmesartan (Benicar) Telmisartan (Micardis) Valsartan (Diovan)

Angiotensin II Receptor Antagonists Losartan Potassium 25 mg TABLETORAL - Losartan Potassium 50 mg TABLETORAL - Losartan Potassium/Hydrochlorothiazide 50/12.5 mg TABLETORAL ( Losartan Potassium 50mg + Hydrochlorothi azide 12.5mg) Valsartan 160 mg CAPSULE ORAL Valsartan 160 mg TABLET ORAL Valsartan 40 mg TABLET ORAL Valsartan 40 mg CAPSULE ORAL Valsartan 80 mg CAPSULE ORAL Valsartan 80 mg TABLET ORAL Eprosartan 300 mg Tablet ORAL Eprosartan 600 mg Tablet ORAL

Renin Angiotensin Aldosterone DrugInitial DoseMax Single Dose ACE- inhibitors Captopril 1.0 mg 4 to 8 mg Enalapril 40 mg 160 to 200 mg Fosinopril 10 mg 100 to 200 mg Lisinopril 2.5 to 5 mg 20 to 40 mg once Perindopril 2 mg once 8 to 16 mg once Quinapril 5 mg twice 20 mg twice Ramipril 1.25 2.5 once 10 mg once Trandolapril 1 mg once 4 mg once Angiotensin Receptor Blocker Candesartan 4 to 8 mg once 32 mg once Losartan 25 to 50 mg once 50 to 100 mg once Candesartan 4 to 8 mg 160 mg twice Aldosterone Antagonists Spironolactone 12.5 to 25 mg 25 mg once or twice Eplerenone 25 mg once 50 mg once

Drug-Induced Acute Renal Dysfunction Acute Renal Failure - Prerenal NSAIDs, CyA/Tacrolimus, ACEI/ARB, Diuretics - Intrinsic ATN vs AIN ATN : Aminoglycosides, Amphotericin B, Radiocontrast Media AIN : B-Lactams, Sulfa, Rifampin, Ciprofloxacin, Cimetidine, NSAIDs, PPIs, Allopurinol, Phenytoin, Diuretics

Acute interstitial nephritis Causes u Medications (AIN occurs >2 weeks after drug started) Penicillins and Cephalosporins PenicillinCephalosporin Hypersensitivity (fever, rash, arthralgia) Sulfonamides Sulfonamide Vasculitis reaction Vasculitis NSAIDs NSAID Nephrotic Syndrome type reaction Nephrotic Syndrome Rifampin, Diuretics (Thiazides and Lasix), Allopurinol, Cimetidine, Ciprofloxacin RifampinDiureticLasixAllopurinolCimetidine Ciprofloxacin Dilantin Dilantin Other medications have caused AIN to a lesser extent u Miscellaneous conditions Glomerulonephritis, Necrotizing Vasculitis, Systemic Lupus Erythematosus GlomerulonephritisVasculitisSystemic Lupus Erythematosus Acute kidney transplant rejection

Acute interstitial nephritis Causes u Infection Diphtheria, Group A beta hemolytic Streptococcus (classic) DiphtheriaStreptococcus Legionella, Yersinia, Staphylococcus or Streptococcus infection LegionellaYersiniaStaphylococcusStreptococcus Mycobacterium, Toxoplasmosis, Mycoplasma, Leptospira MycobacteriumToxoplasmosisMycoplasmaLeptospira Rickettsia, Syphilis, Herpes viruses (e.g. CMV, EBV, HSV) RickettsiaSyphilis Human Immunodeficiency Virus (HIV),Hantavirus Human Immunodeficiency VirusHantavirus Hepatitis C, Mumps Hepatitis CMumps u Medications (AIN occurs >2 weeks after drug started) Penicillins and Cephalosporins PenicillinCephalosporin Hypersensitivity (fever, rash, arthralgia) Sulfonamides Sulfonamide Vasculitis reaction Vasculitis NSAIDs NSAID Nephrotic Syndrome type reaction Nephrotic Syndrome Rifampin, Diuretics (Thiazides and Lasix), Allopurinol, Cimetidine, Ciprofloxacin RifampinDiureticLasixAllopurinolCimetidineCiprofloxacin Dilantin Dilantin Other medications have caused AIN to a lesser extent u Miscellaneous conditions Glomerulonephritis, Necrotizing Vasculitis, Systemic Lupus Erythematosus GlomerulonephritisVasculitisSystemic Lupus Erythematosus Acute kidney transplant rejection Symptoms and Signs u Classic triad (Methicillin induced hypersensitivity)Methicillin Low grade fever (>70% of cases) Rash (>30% of cases) Arthralgia (>15% of cases) u Acute Renal Failure Acute Renal Failure Oliguria Malaise Nausea or Vomiting NauseaVomiting Labs: General u Urinalysis Urinalysis Eosinophiluria Eosinophil Proteinuria Proteinuria Fractional Excretion of Sodium >1% Fractional Excretion of Sodium u Renal Function tests with renal insufficiency Renal Function Serum Creatinine increased Serum Creatinine Blood Urea Nitrogen increased Blood Urea Nitrogen u Miscellaneous Hyperchloremic Metabolic AcidosisMetabolic Acidosis

Dose of Aminoglycosides G,T: 3-5mg/kg/d A: 15-25mg/kg/d S: 1g/d P: 0.5-1g QID N: 1g q4-6h 127

Aminoglycosides Serum concentration - Sampling G & T u Peak: 5-8 mcg/ml u Trough: less 2 mcg/ml A u Peak: 20-30 mcg/ml u Trough: less 10 mcg/ml V u Peak: 15-30 mcg/ml u Trough: less 5-20 mcg/ml Infusion time: G & A 30 min, V 60 min(less 1250 mg), 90 min(more 1250 mg) 128

Antibiotics Aminoglycosides u Trough >2mg/L, repeated course in months nonoliguric ATN u Recommendations: hi OD dose (5-7mg/kg/24h x 2-3wks) is less nephrotoxic and equally effective Follow levels, correct K CrCl > 60, 1-2.5mg/kg Q8H CrCl 40-60, Q12H CrCl 20-40, Q24H CrCl

Obstructive nephropathy: Renal tubular obstruction: Caused by intratubular precipitation of tissue degeneration Products & drugs Diagnosis:Urine uric acid to Cr ratio>1 Prevention and therapy:Hydration,urinary alkalization to PH=7,Allopurinol ARF induced by drugs after muscle necrosis and Nontraumatic rhabdomyolysis(alcohol,heroin,phencyclidine, Lovastatin,cyclosporine,erythromycin,gemfibrozil,niacin) External urinary tract obstructionExternal urinary tract obstruction: Drug therapy may leads to urinary tract obstruction Elder males with prostate hypertrophy and antich,TCAs, Disopyramide,Antiarrhythmia,Cyclophosphamide Use of MESNA

Nephrolithiasis: Renal calculus formation Sulfdiazine:6% Triamterene-H :1/1500 Massive ingestion of magnesium-Trisilicate Magnesium phosphate stones Laxative abuse Ammonium urate stones

Patient outcome: Drug induced renal disease is an important clinical problem For management several guidelines can help : 1. Know the potential nephrotoxicity of diagnostic & therapeutic pharmacologic agents used 2. Compare the potential risks and expected benefits 3. Consider alternative diagnostic and therapeutic approaches 4. Use the lowest dose and shortest course of therapy 5. Monitor 6. Modify therapy if toxicity occurs

Drug-Induced Interstitial Nephritis Abstract: Drug-induced interstitial nephritis (DIN) is characterized by a sudden impairment of renal function and is mainly a result of an immune-mediated reaction after intake of a drug. Many different drugs, such as antibiotics, anticonvulsants, diuretics, proton pump inhibitors, non-steroidal anti-inflammatory drugs and many others, are known to cause DIN. The clinical manifestations are characterized by arthralgias, macular or maculopapular exanthema and fever, together with mild proteinuria, sterile pyuria, and eosinophilia. In many cases the only sign is an asymptomatic increase in serum creatinine. Histopathological analysis shows inflammatory infiltrates in the interstitium, the composition of which differs as a function of different forms of T-cell activation and cytokine production. Consequently, the infiltrate shows mostly T cells, and, dependent on the T-cell function, either a monocyte-rich granulomatous reaction, an eosinophilic or neutrophilic inflammation. Often, plasma cells are present, while glomeruli and vessels are spared. The diagnosis of DIN is confirmed with certainty only by biopsy. The lymphocyte transformation test can demonstrate sensitization to a certain drug, but it is often negative - perhaps because the relevant antigen is a metabolite produced in the endothelial cells of the tubuli. The mainstay of treatment is drug discontinuation; the role of steroids is controversial.

Acute Glomerulonephritis Acute glomerulonephritis refers to a specific set of renal diseases in which an immunologic mechanism triggers inflammation and proliferation of glomerular tissue that can result in damage to the basement membrane, mesangium, or capillary endothelium. Hippocrates originally described the manifestation of back pain and hematuria, which lead to oliguria or anuria. With the development of the microscope, Langhans was later able to describe these pathophysiologic glomerular changes.

Drug-Induced Acute Interstitial Nephritis Acute interstitial nephritis (AIN) is a form of inflammatory renal disease affecting predominantly the tubules and the interstitium. Drugs, particularly -lactam antibiotics and non-steroidal anti-inflammatory drugs, are currently the most common causes. The pathogenesis of drug-induced AIN is complex but there is good clinical evidence for an immune-mediated reaction. Clinical findings may be variable depending on the drug involved and the individual response. Most patients recover from the acute renal failure; however, in older patients or in patients with pre-existing renal insufficiency the recovery of renal function may be incomplete.

Medications (Inhibit tubular secretion of Creatinine) Aminoglycosides Aminoglycoside Cephalosporins Cephalosporin Cefoxitin Cefoxitin Cephalothin Hydantoin Hydantoin Diuretics Diuretic Methyldopa Cimetidine Cimetidine Trimethoprim

Aminoglycoside Risk Factors for Nephrotoxicity? u Advanced age u Prior renal insufficiency u Dehydration u Hypokalemia Hypokalemia u Hypomagnesemia Hypomagnesemia u Liver disease u Sepsis Sepsis

Uric acid is the end-product of purine metabolism and is primarily removed by the kidney. The process of excretion involves filtration, secretion, and reabsorption. Many drugs have been found to alter these processes and induce a state of hyperuricemia. Diuretic- induced hyperuricemia is probably the single most common form of hyperuricemia seen in clinical practice. In most cases, the uric acid level returns to normal after the removal of the offending drug provided there has not been any drug-induced renal injury. Alcohol Amiloride Bumetanide Chorthalidone Cisplatin Cyclophosphamide Cyclosporine Ethacrynic acid Ethambutol Furosemide Hydrochlorothiazide Indapamide Isotretinoin Ketoconazole Levodopa Metolazone Pentamidine (renal damage) Phencyclidine Pyrazinamide Salicylates Theophylline Thiazide diuretics (in addition to the ones listed above) Vincristine

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The best option for a patient with severe pulmonary edema, who remains anuric after trials of 10 and 20 mg/h IV furosemide is: A) Increase the dose of furosemide to 40 mg/h B) Change the furosemide to bolus dosing; start with 200 mg IV C) Add metolazone 5 mg daily D) Discontinue furosemide and begin metolazone 10 mg twice daily E) Change to bumetanide 2 mg/h

Which of the following therapies might worsen fluid or electrolyte disturbances typically present in the patient with ARF? A) Metronidazole 500 mg orally every 6 hours for diarrhea caused by Clostridium difficile B) Monobasic and dibasic sodium phosphate (Fleet Phospho-Soda) 45 mL daily as needed for bowel movement C) Diltiazem 10 mg/h for rate control because of atrial fibrillation D) Sodium polystyrene sulfonate (Kayexalate) 30 g orally once E) All of the above

Prerenal ARF can be exacerbated by the continuation of all of the following medications, except? A) Lisinopril B) Metolazone C) Indomethacin D) Prednisone E) Valsartan

All of the following should be assessed daily in a patient with ARF, except? A) Liver aminotransferases B) Serum creatinine C) Weight D) Medication dosages E) Urine output

Which of the following is not an important consideration when selecting a dosage of a renally eliminated antibiotic in a patient with ARF? A) Cardiac output B) Fluid status C) Renal replacement therapy D) Estimated GFR E) Hemoglobin

A 58-year-old male with unknown past medical history has prerenal acute renal failure from acute blood loss because of a limb amputation in an industrial accident, and aggressive fluid resuscitation is initiated. Which of the following set of monitoring parameters are most appropriate for during the next 8 hours? A) Urine output, rales, and blood pressure B) Heart rate, blood pressure, and BUN C) Bowel sounds, blood pressure, funduscopic findings D) Blood pressure, serum potassium, and serum sodium E) Blood pressure, weight, and blood glucose

The use of serum creatinine as a marker of glomerular filtration rate (GFR) in the setting of ARF is limited by: A) The test is not readily available in most laboratories B) Its lack of responsiveness to abrupt changes in GFR C) Its accuracy increases in the setting of volume overload D) The glomerulus increases its filtration of creatinine during ARF E) Numerous medications cross-react with the assay, rendering the results unreliable

Which if the following is true regarding the treatment of established ARF? A) Dopamine 2 mcg/kg/min is effective to reverse intrinsic ARF B) The liberal use of loop diuretics hasten GFR recovery C) Mannitol is useful to employ in the anuric patient D) The mainstays of therapy are primarily supportive in nature E) Thyroxine is helpful to increase GFR in the elderly patient with subclinical hypothyroidism

For the patient with ARF, goals include: A) Avoid exposure to additional nephrotoxins B) Minimize extrarenal complications C) Expedite recovery of renal function D) Restore previous degree of renal function E) All of the above

In a patient with ARF and gram-negative sepsis receiving gentamicin therapy, which of the following should be considered in developing a treatment regimen? A) Gentamicin removal can be faster in ARF compared to CKD B) Administration of the gentamicin immediately post the intermittent hemodialysis session C) Careful assessment of the patients actual volume of distribution of gentamicin D) Determining the viability of other antimicrobial alternatives E) All of the above

Which of the following is false regarding ARF in the hospitalized patient? A) Occurs in approximately 7% of hospitalized patients B) Is associated with increased mortality C) Can lead to long-term kidney damage and life-long hemodialysis D) Should be aggressively treated with high-dose diuretics

Causes of diuretic resistance include the following except: A) Inappropriate diuretic dose or regimen B) NSAID-associated decrease in sodium resorption C) Presence of heart failure D) Vasodilator-associated reduction in renal blood flow 19

Causes of diuretic resistance include the following except: A) Inappropriate diuretic dose or regimen B) NSAID-associated decrease in sodium reasorption C) Presence of heart failure D) Vasodilator-associated reduction in renal blood flow 19

A 76-year-old, 60-kg patient with a history of heart failure is admitted for severe nausea and fever of several days duration, as well as acute onset of chest pain. There is a single serum creatinine value of 2.4 mg/dL, and tests for several drugs eliminated primarily by the kidney are ordered. It is 2:00 in the afternoon. Choose the best consideration for those agents eliminated primarily by the kidney.

A) The creatinine clearance can be calculated to estimate a GFR, and then an adjusted dosing regimen should implemented for the duration of this admission. B) Send out the initially ordered doses immediately and do not check if any were administered in the emergency room. C) Assess if any drugs were recently administered, and only recommend one day of new therapies if not already started; request a second serum creatinine value to assess if the patients renal function is stable; check to see if the patient is producing any urine as a additional assessment of renal function. D) Assess if any drugs were recently administered, and send out one dose.

In continuous renal replacement therapy (CRRT), the following is true: A) Goal of therapy in CRRT is a ultrafiltration rate of 25 mL/h/kg B) Thrombosis is a concern where anticoagulation can be necessary C) Requires specialized staff and equipment D) Is frequently used in unstable patients where IHD can increase the risk of a hypotensive episode E) All the above

The most common manifestation of drug-induced kidney disease is: A) Proteinuria B) Pyuria C) Hematuria D) A decline in the glomerular filtration rate (GFR) E) A reduction in tubular secretion

Regarding drug-induced kidney disease, all of the following are applicable except: A) Temporal relationship with potentially toxic agent B) The offending agent is rarely identified C) Significant source of morbidity in the hospital setting D) Abrupt and sustained reduction in GFR E) The most common presentation in the hospital setting is acute tubular necrosis

Which of the following drugs would be the most likely culprit in a patient with newly diagnosed renal intratubular obstruction? A) Ibuprofen B) Losartan C) Amphotericin B D) Ciprofloxacin E) Acyclovir

Hemodynamically mediated renal failure induced by angiotensin-converting enzyme inhibitors (ACEI) involves all of the following except: A) Enhanced efferent arteriolar constriction B) Patients with renal artery stenosis at increased risk C) Decrease in glomerular capillary hydrostatic pressure D) Reduced glomerular ultrafiltration E) None of the above

Which of the following drugs has been associated with chronic interstitial nephritis? A) Cyclosporine B) Ifosfamide C) Lithium D) Streptozotocin E) All of the above

Which of the following drugs has been associated with collapsing glomerulosclerosis? A) Propylthiouracil B) Aminoglycosides C) Pamidronate D) Radiographic contrast media E) Hydralazine

The following renal structural-functional alteration is associated with exposure to radiographic contrast media: A) Allergic interstitial nephritis B) Intratubular obstruction C) Glomerulosclerosis D) Acute tubular necrosis E) Papillary necrosis

All of the following strategies can be used to prevent radiographic contrast media nephrotoxicity except: A) Amifostine B) Acetylcysteine C) Low osmolality agents D) Hydration E) Reduced doses of contrast

The preferred agent for preventing cisplatin-induced nephrotoxicity is: A) Fenoldopam B) Amifostine C) Dopamine D) Acetylcysteine E) Mesna

All of the following drugs are linked to the development of antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis except: A) Hydralazine B) Allopurinol C) Warfarin D) Propylthiouracil E) Penicillamine

Each of the following statements regarding aminoglycoside-induced acute tubular necrosis is true except: A) Risk factors include prolonged therapy and increased age B) It manifests as a gradual increase in serum creatinine 4 to 6 weeks after exposure to the drug C) Patients typically present with nonoliguria, maintaining urine volumes greater than 500 mL/day D) Toxicity of various aminoglycosides is related to cationic charge of the drug E) Once-daily dosing is one method to maintain antimicrobial efficacy while reducing nephrotoxicity 12

Each of the following statements regarding aminoglycoside-induced acute tubular necrosis is true except: A) Risk factors include prolonged therapy and increased age B) It manifests as a gradual increase in serum creatinine 4 to 6 weeks after exposure to the drug C) Patients typically present with nonoliguria, maintaining urine volumes greater than 500 mL/day D) Toxicity of various aminoglycosides is related to cationic charge of the drug E) Once-daily dosing is one method to maintain antimicrobial efficacy while reducing nephrotoxicity

The preferred treatment for a patient with drug- induced minimal change glomerular injury accompanied by interstitial nephritis is: A) Amifostine B) Cyclophosphamide C) Pamidronate D) Prednisone E) Hydration

The signs and symptoms of penicillin-induced allergic interstitial nephritis include all of the following except: A) Rash, eosinophilia, pyuria B) Fever, eosinophilia, reduced intraglomerular pressure C) Fever, rash, eosinophilia D) Elevated serum creatinine, rash, eosinophilia E) Hematuria, proteinuria, oliguria

A 60-year-old woman with a 5-year history of NSAID use is prescribed enalapril and develops acute renal failure. What is the most likely cause of her renal failure? A) Acute allergic interstitial nephritis B) Chronic interstitial nephritis C) Minimal change glomerular injury D) Focal segmental glomerulosclerosis E) Hemodynamically-mediated renal failure

Potential causes of pseudo-renal failure include all of the following except: A) Competitive inhibition of creatinine tubular secretion by cimetidine B) Drug induced increase in protein catabolism C) Direct interference with the enzymatic measurement of creatinine D) Increased synthesis and release of creatinine into serum E) Competitive inhibition of creatinine tubular secretion by trimethoprim

Glomerulonephritis

In a patient with nephrotic syndrome, which of the following is not expected to be present? A) Proteinuria B) Edema C) Hyperlipidemia D) Hypercoagulable state E) Hematuria

Which of the following is not expected to reduce proteinuria when used for patients with glomerulonephritis? A) Angiotensin-converting enzyme (ACE) inhibitors B) Angiotensin II receptor blockers C) Nondihydropyridine calcium channel blockers (e.g., diltiazem) D) Dihydropyridine calcium channel blockers (e.g., nifedipine, amlodipine) E) All of the above are expected to reduce proteinuria

Treatment of which of the following is expected to reduce the progression of renal failure in patients with glomerulonephritis? A) Edema B) Proteinuria C) Hyperlipidemia D) Coagulopathy E) Hematuria

ACE inhibitors are often used in patients with glomerulonephritis because of their ability to reduce: A) Proteinuria B) Blood pressure C) Immunologically induced glomerular damage D) Both A and B E) All A, B, and C

Intravascular thrombosis is a common and serious complication of nephrotic syndrome associated with which of the following glomerular disease? A) Minimal-change nephropathy B) Focal segmental glomerulonephritis C) Membranous nephropathy D) Immunoglobulin A nephropathy E) Membranoproliferative glomerulonephritis

Which of the following glomerulonephritis is more commonly seen in pediatric patients? A) Minimal-change nephropathy B) Focal segmental glomerulonephritis C) Immunoglobulin A nephropathy D) Membranous nephropathy E) Membranoproliferative glomerulonephritis

Which of the following agent is known to be most effective in inducing remission in patients with recently diagnosed minimal-change nephropathy? A) Steroid B) Cyclosporine C) Azathioprine D) Cyclophosphamide E) Levamisole

Which of the following is not correct regarding the use of cyclosporine for the treatment of minimal-change nephropathy? A) Cyclosporine may reduce lymphokine production by activated T lymphocytes B) Cyclosporine may improve the permselectivity of GBM C) Cyclosporine is often effective in preventing relapse D) Cyclosporine is often effective in inducing remission during relapse E) Cyclosporine is useful for patients who are steroid dependent

Compared with minimal-change nephropathy, patients with focal segmental glomerulonephritis are: A) More likely to be adults B) Less responsive to steroid treatment C) More likely to develop progressive renal failure D) Only A and B above are correct E) All A, B, and C above are correct

In patients with mild focal segmental glomerulonephritis, which of the following is (are) commonly used? A) ACE inhibitors B) Angiotensin II receptor blockers C) Immunosuppressive agents D) Both A and/or B can be used E) All A, B, and C are necessary to induce remission

Fish oil may be beneficial in certain patients with which of the following types of glomerulonephritis? A) Minimal-change nephropathy B) Focal segmental glomerulonephritis C) Immunoglobulin A nephropathy D) Membranous nephropathy E) Membranoproliferative glomerulonephritis

Which of the following is correct with respect to treatment for membranous nephropathy? A) Spontaneous remission is common, and steroid treatment alone is commonly used to reduce proteinuria and progression of disease B) Spontaneous remission is common, and steroid treatment alone is not effective in reducing proteinuria and progression of disease C) Spontaneous remission is unlikely, and steroid treatment is needed to reduce proteinuria and progression of disease D) Spontaneous remission is unlikely, and steroid treatment alone is not effective in reducing proteinuria and progression of disease E) Steroid and cytotoxic agents are commonly needed to induce remission

A patient with IgA nephropathy who has normal renal function, isolated micro-hematuria, and proteinuria less than 1 g/day should be: A) Observed closely without specific treatment B) Given fish oil C) Given steroid treatment D) Given cytotoxic agents E) Given cyclosporine

Which of the following is not normally considered when selecting the optimal treatment for patients with lupus nephritis? A) Type of underlying lesion B) Disease activity according to pathologic findings C) Severity of symptoms D) Duration of symptoms E) All of the above are commonly considered

Which of the following is frequently used for chronic maintenance treatment of lupus nephritis? A) Steroid B) Cytotoxic agent C) Cyclosporine D) Mycophenolate mofetil E) Fish oil

Monoclonal antibodies has been evaluated for the treatment of which of the following glomerular disease? A) Minimal-change nephropathy B) Focal segmental glomerulonephritis C) IgA nephropathy D) Lupus nephritis E) Poststreptococcal glomerulonephritis

The presence of crescents in glomeruli of patients with rapidly progressive glomerulonephritis (RPGN) indicates: A) Severe disease requiring early aggressive therapy B) Type I RPGN C) Type II RPGN D) Type III RPGN E) The need for close observation but no specific treatment

Which of the following is (are) known to cause glomerulonephritis? A) Group A streptococci B) Hepatitis C virus C) HIV D) Parasites E) All of the above

Antibiotic treatment after poststreptococcal glomerulonephritis may: A) Prevent subsequent poststreptococcal glomerulonephritis B) Reduce severity of disease C) Prevent the spread of infection to family members D) Both B and C E) Both A and C

Drug Therapy Individualization with Renal Insufficiency

Which of the following is the predominant mechanism by which the bioavailability of some drugs is increased in patients with severe stage 5 chronic kidney disease? A) Decreased renal clearance B) Decreased first-pass metabolism C) Increased volume of distribution D) Increased plasma protein binding

Which of the following drugs will most likely have an increased fraction unbound in patients with end-stage renal disease (ESRD)? A) Clonidine B) Disopyramide C) Phenytoin D) Propafenone

Unbound drug concentrations for drugs that are highly protein bound should not be used to monitor therapy and make dose modifications in patients with chronic kidney disease. A) True B) False

The metabolism of many drugs is altered in patients with renal insufficiency. Select which of the following statements is true regarding this phenomenon: A) The onset of the effect on metabolism is rapid, thus there is no difference between patients with acute and chronic kidney disease B) The observed reductions in nonrenal clearance in CKD patients are not proportional to the reductions in glomerular filtration rate (GFR) C) The effect on metabolism is greater in patients with ARF than in patients with ESRD D) Data suggest a differential effect on the individual CYP450 enzymes with the activity of some enzymes being reduced, although the activity of other enzymes is not affected E) The degree of increase in drug metabolism is highly variable

Which of the following statements regarding renal drug excretion is true? A) The P-glycoprotein transport system in the kidney is also involved in the tubular secretion of anionic drugs B) The decrease in renal drug clearance for drugs that are primarily secreted will be proportional to the reduction in glomerular filtration rate C) The renal clearance (CLr) of a drug that undergoes secretion (CLr >300 mL/min) is likely to be reduced more in a patient with glomerulonephritis than in one with tubulointerstitial renal disease D) A patient with acute tubular necrosis will have lower - lactam renal clearance than a patient with chronic glomerulonephritis (assuming comparable CLcr)

An HIV-infected patient who has a creatinine clearance (CLcr) of 34 mL/min is to receive tenofovir for the treatment of human immunodeficiency virus (HIV) infection (in combination with other antiretroviral agents). After intravenous administration of tenofovir, approximately 75% of the dose is recovered in the urine as unchanged drug. Based on this information, calculate the most appropriate dosing interval for this patient with impaired renal function. Assume the normal dosing interval (TN) is every 24 hours. A) 12 hours B) 24 hours C) 36 hours D) 48 hours E) 72 hours

A 72-year-old, 65-kg man is to receive ciprofloxacin. The usual dose of ciprofloxacin is 500 mg twice daily for patients with normal renal function. Calculate a new dose to be given every 12 hours. The patients measured CLcr is 48 mL/min, and the relationship between ciprofloxacin oral clearance (CL/F) and renal function is CL/F (mL/min) = 2.83 (CLcr) + 363. A) 125 mg every12 hours B) 250 mg every 12 hours C) 375 mg every 12 hours D) 500 mg every 12 hours

A.C. is to receive amoxicillin for a suspected urinary tract infection. His measured CLcr is 45 mL/min, and the clearance and fraction of drug eliminated renally unchanged of amoxicillin in a patient with normal renal function (CLcr = 120 mL/min) are 221 mL/min and 86%, respectively. What do you project his clearance of amoxicillin will be? A) 150 mL/min B) 119 mL/min C) 102 mL/min D) 83 mL/min E) 19 mL/min

Which of the following statements concerning the relative efficiency of drug removal by dialysis is false? A) Peritoneal dialysis is less effective than hemodialysis at removing drug substances B) High-flux hemodialysis drug clearances are greater in ARF patients than in CVVHD C) The clearance (mL/min) values of all drugs with continuous renal replacement therapies are smaller than the values reported with conventional hemodialysis D) CVVH clearance of a given drug always will be less than CVVHDF clearance E) Conventional hemodialysis produces greater removal of most drugs when compared with high-flux hemodialysis

Which of the following drugs is least likely to be removed by conventional hemodialysis (i.e., hemodialysis using a cellulose membrane)? A) Foscarnet (MW = 94; Vd = 0.7 1/kg; Fraction bound = 0.17) B) Cefazolin (MW = 454; Vd = 0.2 1/kg; Fraction bound = 0.50) C) Ceftriaxone (MW = 450; Vd = 0.2 1/kg; Fraction bound = 0.90) D) Inulin (MW = 5,200; Vd = 0.05 1/kg; Fraction bound = 0.00)

Which of the following is the optimal approach to determine the effect of hemodialysis on the pharmacokinetics of a new drug? A) Determine the half-life of the drug during dialysis and compare with the value observed in those with normal renal function B) Calculate the recovery clearance, CL = amount in dialysate/AUC0-t in serum during dialysis C) Collect the dialysate and calculate the ratio of the concentration of the drug in dialysate to concentration of drug in blood D) Measure the blood clearance, CLblood = Qb[(CLarterial CLvenous)/CLarterial] E) Determine the total-body clearance of the drug when administered on a nondialysis day relative to the total-body clearance observed when the drug is given during dialysis

T.D. is a 34-year-old, 60-kg man with a residual CLcr of 8 mL/min who has been receiving hemodialysis for 3 months. He was just started on gabapentin 300 mg orally every 8 hours by his neurologist. What dosage regimen would you recommend given that the volume of distribution is 0.7 L/kg, the fraction eliminated in the urine unchanged is 90%, and protein binding is 3%? A) 300 mg every 8 hours B) 150 mg every 8 hours C) 50 mg every 8 hours D) 300 mg every 24 hours E) 300 mg every 48 hours

S.M. is a 58-year-old, 75-kg man with a residual CLcr of 9 mL/min who has been receiving hemodialysis for 9 months. His nephrologist wants to start him on gentamicin (initial dose 150 mg IV over 0.5 hours) to treat an infected foot. What do you project his serum concentration will be in 40 hours, just prior to his next dialysis session, given that the volume of distribution is 0.3 L/kg, the CLgentamicin = CLcr 0.983, and protein binding is 3%? A) 8.3 mg/L B) 6.6 mg/L C) 4.8 mg/L D) 2.5 mg/L E) 1.8 mg/L

If the serum gentamicin concentration was determined to be 3.6 mg/L, what do you project S.M.s gentamicin serum concentration will be after 4 hours of dialysis with a high- flux dialyzer for which the reported gentamicin clearance is 116 mL/min? A) 0.7 mg/L B) 1.1 mg/L C) 1.6 mg/L D) 2.0 mg/L E) 2.5 mg/L 15

The serum gentamicin concentration after the end of dialysis is determined to be 1.8 mg/L. What is the supplemental dose that should be given to achieve a target peak concentration of 8 mg/L? Calculate the dose using the simplified approach. A) 75 mg B) 90 mg C) 110 mg D) 220 mg

Which of the following is the most common cause of intrinsic ARF? A) Tubular damage from aminoglycoside use B) Glomerular damage from severe inflammation C) Tubular damage from prolonged ischemia D) Occlusion of the renal vasculature

The best option for a patient with severe pulmonary edema, who remains anuric after trials of 10 and 20 mg/h IV furosemide is: A) Increase the dose of furosemide to 40 mg/h B) Change the furosemide to bolus dosing; start with 2

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24/10/1436 Drug induced nephrotoxicity Naser Hadavand