drug induced nephrotoxicity

*Drug induced nephrotoxicity

Naser Hadavand

DefinitionsType Onset SeverityClassification of Drug Induced Disordres

Definition and Classifications of Adverse Reaction TermsAdverse Event:

Adverse Drug Reaction:

Side Effect:

Definition and Classifications of Adverse Reaction TermsAdverse 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.


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.

ExamplesAdverse Event:

Adverse Drug Reaction:

Side Effect:

Adverse Drug Reaction vs. Adverse EventAdverse Drug Reaction(event attributed to drug)Adverse EventAll Spontaneous reports

Events not attributed to drug DiseasesOther DrugsEnvironmentDietGeneticsComplianceOther factors

DefinitionsType Onset SeverityClassification

Comparison Type A and Type B

A

B

Pharmacologically predictable

Yes

No

Dose-dependent

Yes

No

Incidence and morbidity

High

Low

Mortality

Low

High

Treatment

Adjust dose

Stop

Adverse Drug ReactionsUnwanted effects of drugs are separated into those represent: Augmented pharmacological effects of a substance but qualitatively normal (Type A)Qualitatively bizarre pharmacological effects (Type B)Long term effects (Type C)Delayed effects (Type D)End of use (Type E)Failure (Type F)

* Most long term effects are Type A reactions.

IntroductionOccurs 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% .

IncidenceFrequent 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 FailureInterstitial NephritisAcute interstitial nephritisChronic interstitial nephritisAcute GlomerulonephritisAcute Tubular NecrosisCrystal nephropathyRhabdomyolysisNephrotic 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.

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. In chronic tubulointerstitial nephritis: nausea, vomiting, fatigue, and weight loss. hyperkalemia, metabolic acidosis, and kidney failure.Blood tests: Eosinophilia, Cr & BUNUrinary findings: Eosinophiluria, Isosthenuria, hematuria, Sterile pyuria: white blood cells and no bacteria

Acute interstitial nephritisSymptoms and SignsClassic triad (Methicillin induced hypersensitivity)Low grade fever (>70% of cases)Rash (>30% of cases)Arthralgia (>15% of cases)Acute Renal Failure OliguriaMalaiseNausea or VomitingLabs: GeneralUrinalysis EosinophiluriaProteinuria Fractional Excretion of Sodium >1%Renal Function tests with renal insufficiencyCr & BUN increasedMiscellaneousHyperchloremic Metabolic Acidosis

Acute interstitial nephritisCausesInfectionDiphtheria , Group A beta hemolytic Streptococcus (classic)Legionella , Yersinia , Staphylococcus or Streptococcus infectionMycobacterium , Toxoplasmosis , Mycoplasma , Leptospira Rickettsia , Syphilis , Herpes viruses (e.g. CMV, EBV, HSV)Human Immunodeficiency Virus (HIV),Hantavirus Hepatitis C , Mumps Medications (AIN occurs >2 weeks after drug started)Penicillins and CephalosporinsHypersensitivity (fever, rash, arthralgia)SulfonamidesVasculitis reactionNSAIDsNephrotic Syndrome type reactionRifampin , Diuretics (Thiazides and Lasix), Allopurinol , Cimetidine , Ciprofloxacin Dilantin Other medications have caused AIN to a lesser extentMiscellaneous conditionsGlomerulonephritis , Necrotizing Vasculitis, Systemic Lupus Erythematosus Acute kidney transplant rejectionSymptoms and SignsClassic triad (Methicillin induced hypersensitivity)Low grade fever (>70% of cases)Rash (>30% of cases)Arthralgia (>15% of cases)Acute Renal Failure OliguriaMalaiseNausea or VomitingLabs: GeneralUrinalysis EosinophiluriaProteinuria Fractional Excretion of Sodium >1%Renal Function tests with renal insufficiencySerum Creatinine increasedBlood Urea Nitrogen increasedMiscellaneousHyperchloremic Metabolic 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.

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.

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.

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.

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. 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. 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. 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.

Definitions:Nephrotic Syndrome Nephrotic syndrome is a nonspecific kidney disorder characterised by a number of diseases: proteinuria, hypoalbuminemia and edema. It is characterized by an increase in permeability of the capillary walls of the glomerulus leading to the presence of: - high levels of protein passing from the blood into the urine (proteinuria at least 3.5 grams per day per 1.73m2 body surface area); - low levels of protein in the blood (hypoproteinemia or hypoalbuminemia), - Ascites and edema - High cholesterol (hyperlipidaemia or hyperlipemia) - Predisposition for coagulation. Kidneys affected by nephrotic syndrome have small pores in the podocytes, large enough to permit proteinuria (and subsequently hypoalbuminemia,

Diagnosis:

Proteinuria: >3.5g/dHypoalbuminemia: 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). 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 outputOliguric: 50-400ml/day urine outputNon-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/dL2.5 - 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 >20Post Renal: BUN/ Cr 10 20Renal: 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> +13Marked9 to 13Moderate6 to 9Mild4 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 FUNCTIONCockcroft and Gault Equation:

Estimates renal function when creatinine levels are at steady-statenot usually the case in acute renal failureCLCr(ml/min) = (140-Age)(Wt.) 72(Scr)

= 0.85 (female)

Serum CreatinineCreatinine 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

Estimate Ideal body weight in (kg) Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet. Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet. Adjusted body weight (ABW): ABW = IBW + 0.4(Total body weight - IBW)

Normal Blood GasesArterialVenouspH7.35 - 7.457.32 - 7.42Not 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 HgThe 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)HCO322 to 26 mEq/liter (2128 mEq/L)19 to 25 mEq/literThe calculated value of the amount of bicarbonate in the bloodstream. Not a blood gas but the anion of carbonic acid.PaCO2 35-45 mm Hg38-52 mm HgThe 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+ + HCO3B.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 acidosisSaO295% to 100%50 - 70%The arterial oxygen saturation.

DefinitionsType 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

Relative Serum Creatinine increase 50% over baseline Absolute Serum Creatinine increase Serum Creatinine baseline 2 mg/dl: Creatinine increase 1.0 mg/dl over baseline

Drug-Induced Acute Renal DysfunctionPseudo 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

Mechanism

Drug(s)

Reduction of renal perfusion

NSAIDs, ACE-inhibitors,cyclosporine, tacrolimus, amphotericin B

Direct tubular toxicity

Aminoglycosides, radiocontrast agents, cyclosporine, tacrolimus, amphotericin B, pentamidine, cisplatin

Allergic interstitial nephritis

Penicillins, cephalosporins, sulfonamides, NSAIDs

Intratubular obstruction by precipitation

Acyclovir, sulfonamides, chemotherapeutics

ETIOLOGY: pre-renal

Decreased cardiac output: CHF,MI,PE, Beta-blockers

Peripheral vasodilation: bacterial sepsis, vasodilators (nitrates, hydralazine,etc.)

Hypovolemia: blood loss,Severe dehydration, diarrhea, burns, third-spacing, diuresis(diuretics)

Vascular Obstruction: NSAIDS, ACE-I, Vasopressors, renal artery occlusion

(NSAIDs)

History 1The first reference to aspirin was by a 5th 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 2Sodium 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 3In the 1990's an important discovery was made from elegant molecular and cellular biological studies that there are two cyclo-oxygenase (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 4While 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.

AspirinCelecoxibDiclofenacIndomethacinIbuprofenKetorolacMefenamic acidNaproxenSulindacSalicylic acidPiroxicamTolmetinSodium salicylateIndomethacinNaproxen

Endothelium, brain, spinal cord Kidney (Macula densa), ovaries, uterusN.B.: COX-2 also in

+GCSClassical 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).

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.

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.

NSAIDs are also used in the acute pain caused by gout because they inhibit urate crystal phagocytosis besides inhibition of prostaglandin synthase.

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.

Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the 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). Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D & E.

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,

Drug interactions

NSAIDs reduce renal blood flow and thereby decrease the efficacy of diuretics, and inhibit the elimination of lithium and methotrexate.

NSAIDs cause hypocoagulability, which may be serious when combined with other drugs that also decrease blood clotting, such as warfarin.

NSAIDs may aggravate hypertension (high blood pressure) and thereby antagonize the effect of antihypertensives, such as ACE Inhibitors.

NSAIDs may interfere and reduce efficiency of SSRI antidepressants

IndicationsNSAIDs 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.NSAIDs are generally indicated for the symptomatic relief of the following conditions:Rheumatoid arthritis OsteoarthritisInflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome)Acute gout Dysmenorrhoea (menstrual pain)Metastatic bone pain Headache and migrainePostoperative pain Mild-to-moderate pain due to inflammation and tissue injuryMuscle stiffness and pain due to Parkinson's diseasePyrexia (fever) Ileus Renal colic Ductus arteriosus is not closed within 24 hours of birthAspirin, 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 A2.

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

NSAIDs 10-1% NSAIDs ( ) ACE ( )

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

NSAIDs Sulindac

Naproxen

Analgesic nephropathyAnalgesic 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. - Result: decreased blood flow to the kidney, rapid consumption of antioxidants, and subsequent oxidative damage to the kidney. This kidney damage may lead to progressive chronic renal failure, abnormal urinalysis results, high blood pressure, and anemia.

Analgesic nephropathyCauses, 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.

- 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 nephropathyRisk 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 nephropathySymptoms There may be no symptoms. Symptoms of chronic kidney disease are often present over time and may include:Weakness, FatigueIncreased urinary frequency or urgencyBlood in the urineFlank pain or back painDecreased urine outputDecreased alertness : Drowsiness , Confusion, delirium , LethargyDecreased sensation, numbness (especially in the legs)Nausea, vomitingEasy bruising or bleedingSwelling, generalized

Analgesic nephropathySigns and testsA physical examination may show signs of interstitial nephritis or kidney failure.Blood pressure may be highabnormal heart or lung sounds There may be signs of premature skin agingLab 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.Tests that may be done include: - CBC - sedimentation in the urine - Intravenous pyelogram(IVP) - Toxicology screen - Urinalysis

Analgesic nephropathyTreatmentThe 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.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 nephropathyComplicationsAcute renal failureChronic renal failureInterstitial nephritisRenal papillary necrosis (tissue death)Urinary tract infections, chronic or recurrentHypertensionTransitional cell carcinoma of the kidney or ureter

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

Cyclosporine, TacrolimusCan 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/CrAngiographyBiopsy

Side Effects

Putting Guidelines into Practice

ACE INHIBITORS ACE Inhibitors In Whom and When?Indications:Potentially all patients with heart failureFirst-line treatment (along with beta-blockers) in NYHA class IIV heart failureContra-indications: History of angioneurotic oedemaCautions/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 alterationPsuedo renal failure

Hemodynamically mediated renal failureRenal vascular alterationsGlomerular alterationAcute tubular necrosisTubulointerstitial diseaseObstructive nephropathyNephrolithiasis

Increase in BUN and Cr without a decrease in GFRIncrease in BUN and Cr=normCorticosteroid,TC(these increase protein catabolismIncrease in Cr,BUN=normTMP,Pyrimethamine,CimetidineReduction glumerular capillary hydrostatic pressureInhibition of prostaglandin-dependant renal blood flowNonspecific renal vasoconsIncrease vascular permeabilityIncrease in colloid oncotic pressure

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

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

Acute Renal Failure:

PRE-RENAL

ACEI/ARBNSAIDsDiureticsImmunosuppressives (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 & ARBsUremia, hyper K, dialysis dependenceCr > 3.5 consult nephrology!Avoid in bilat renal artery stenosis - ARB causes less renal failure than ACE InhibitorStrategy: BP, K, Crdiuretic holiday x days before startstart captopril 1st, then long-actingRamipril: CrCl < 40, give 25% of normal doseLosartan: 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


ACE INHIBITORS ACE Inhibitors How to UseStart with a low dose Double dose at not less than two weekly intervalsAim for target dose or, failing that, the highest tolerated doseRemember some ACE inhibitor is better than no ACE inhibitorMonitor blood chemistry (urea, creatinine, K+) and blood pressureWhen to stop up-titration/down-titration see PROBLEM SOLVING


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


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 soughtBlood 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 .

ACEIs - Additional ConsiderationsCompelling indications: DM, HF, post-MI, high risk CAD, chronic kidney disease, recurrent stroke prevention (6 of 7)

May have unfavorable effects on: hyperkalemia

Contraindicated in pregnancy

ReceptorsAngiotensin Receptor Blocker: Mechanism of ActionAT II Receptor BlockerAntiproliferative ActionVasodilationProliferative ActionVasoconstrictionATIIATIAngiotensinogenOther PathwaysReninAT I Receptor BlockerAngiotensin IAngiotensin IIACE

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

Angiotensin II Receptor Antagonists

Losartan Potassium 25 mgTABLETORAL-Losartan Potassium 50 mgTABLETORAL-Losartan Potassium/Hydrochlorothiazide 50/12.5 mgTABLETORAL( Losartan Potassium 50mg + Hydrochlorothiazide 12.5mg)

Valsartan 160 mgCAPSULEORALValsartan 160 mgTABLETORALValsartan 40 mgTABLETORALValsartan 40 mg CAPSULEORALValsartan 80 mgCAPSULEORALValsartan 80 mgTABLETORAL

Eprosartan 300 mgTabletORALEprosartan 600 mgTabletORAL

Renin Angiotensin Aldosterone

DrugInitial DoseMax Single DoseACE- inhibitorsCaptopril1.0 mg4 to 8 mgEnalapril40 mg160 to 200 mgFosinopril10 mg100 to 200 mgLisinopril2.5 to 5 mg20 to 40 mg oncePerindopril2 mg once8 to 16 mg onceQuinapril5 mg twice20 mg twiceRamipril1.25 2.5 once10 mg onceTrandolapril1 mg once4 mg onceAngiotensin Receptor BlockerCandesartan4 to 8 mg once32 mg onceLosartan25 to 50 mg once50 to 100 mg onceCandesartan4 to 8 mg160 mg twiceAldosterone AntagonistsSpironolactone12.5 to 25 mg25 mg once or twiceEplerenone25 mg once50 mg once


- Intrinsic ATN vs AIN ATN : Aminoglycosides, Amphotericin B, Radiocontrast Media AIN : B-Lactams, Sulfa, Rifampin, Ciprofloxacin, Cimetidine, NSAIDs, PPIs, Allopurinol, Phenytoin, Diuretics

Acute interstitial nephritisCausesMedications (AIN occurs >2 weeks after drug started)Penicillins and CephalosporinsHypersensitivity (fever, rash, arthralgia)SulfonamidesVasculitis reactionNSAIDsNephrotic Syndrome type reactionRifampin , Diuretics (Thiazides and Lasix), Allopurinol , Cimetidine , Ciprofloxacin Dilantin Other medications have caused AIN to a lesser extentMiscellaneous conditionsGlomerulonephritis , Necrotizing Vasculitis, Systemic Lupus Erythematosus Acute kidney transplant rejection

Acute interstitial nephritisCausesInfectionDiphtheria , Group A beta hemolytic Streptococcus (classic)Legionella , Yersinia , Staphylococcus or Streptococcus infectionMycobacterium , Toxoplasmosis , Mycoplasma , Leptospira Rickettsia , Syphilis , Herpes viruses (e.g. CMV, EBV, HSV)Human Immunodeficiency Virus (HIV),Hantavirus Hepatitis C , Mumps Medications (AIN occurs >2 weeks after drug started)Penicillins and CephalosporinsHypersensitivity (fever, rash, arthralgia)SulfonamidesVasculitis reactionNSAIDsNephrotic Syndrome type reactionRifampin , Diuretics (Thiazides and Lasix), Allopurinol , Cimetidine , Ciprofloxacin Dilantin Other medications have caused AIN to a lesser extentMiscellaneous conditionsGlomerulonephritis , Necrotizing Vasculitis, Systemic Lupus Erythematosus Acute kidney transplant rejectionSymptoms and SignsClassic triad (Methicillin induced hypersensitivity)Low grade fever (>70% of cases)Rash (>30% of cases)Arthralgia (>15% of cases)Acute Renal Failure OliguriaMalaiseNausea or VomitingLabs: GeneralUrinalysis EosinophiluriaProteinuria Fractional Excretion of Sodium >1%Renal Function tests with renal insufficiencySerum Creatinine increasedBlood Urea Nitrogen increasedMiscellaneousHyperchloremic Metabolic 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*

AminoglycosidesSerum concentration - SamplingG & TPeak: 5-8 mcg/mlTrough: less 2 mcg/mlAPeak: 20-30 mcg/mlTrough: less 10 mcg/mlVPeak: 15-30 mcg/mlTrough: less 5-20 mcg/ml

Infusion time: G & A 30 min, V 60 min(less 1250 mg) , 90 min(more 1250 mg)

*

Antibiotics AminoglycosidesTrough >2mg/L, repeated course in months nonoliguric ATNRecommendations: hi OD dose (5-7mg/kg/24h x 2-3wks) is less nephrotoxic and equally effectiveFollow levels, correct KCrCl > 60, 1-2.5mg/kg Q8HCrCl 40-60, Q12HCrCl 20-40, Q24HCrCl

Neomycin< Gentamicin,Tobramycin > Netilmicin,Streptomycin

Risk factor for Aminoglycoside NephrotoxicityRelated to AMG dosingLarge total cummulative doseProlong therapyHigh peak or trough conc.Recet previous AMG therapyRelated to Predisposing condition in the patientPreexisting renal insufficiencyIncreased agePoor nutritionShockGramnegative bactermiaLiver diseaseHypoalbuminemisObstructive jaundiceK+ or Mg++ deficiency

Related to synergistic nephrotoxicity AMG combination withCyclosporinAmphotericin BVancomycinDiureticsIrreversible Damage!

Aminoglycoside NephrotoxicityPrevention Switching to alternative antibiotics Avoid volume depletion, concomitant therapy with other nephrotoxic drugs Limit total dose Decreasing the frequency of AMG dosing to at least daily (as direct by renal clearance)Management Monitor Scr, concentration, renal fn and electrolytes Discontinue AMG if changes are seen.

AminoglycosideDrug interactions with other nephrotoxic medications:Cephalothin and other CephalosporinsCyclosporin ACisplatinNSAIDsACE InhibitorsLoop DiureticsAmino acids

Amphotericin B nephrotoxicity

Dose dependant RBF & GFR SCr,concentrate urine and K,Na,Mg wasting

Risk factors: Higher average daily doses ,diuretic use, Volume depletion

Prevention: Limiting the doseVolume repletion Amphotericin+IV saline Liposomal amphotericin with lipidsCCBsDiscontinuation

Drug-induced nephrotoxicity caused by amphotericin B lipid complex and liposomal amphotericin B: a review and meta-analysis.

Lipid preparations of amphotericin B, commonly used to treat fungal infections, have been demonstrated to have reduced nephrotoxicity compared to conventional amphotericin B. However, to our knowledge, a comprehensive comparison of nephrotoxicity induced by different lipid preparations of amphotericin B has not been performed. We conducted a meta-analysis to evaluate nephrotoxicity associated with amphotericin B lipid complex (ABLC) and liposomal amphotericin B (L-AmB). We searched the PubMed MEDLINE database and abstracts presented at key scientific meetings, and identified 11 studies reported between 1995 and 2008 that compared nephrotoxicity resulting from the use of these agents. Eight of the 11 studies were included in the meta-analysis. The Cochran-Mantel-Haenszel test was used to determine odds ratio (OR) and relative risk (RR), and the Breslow-Day test was used to analyze homogeneity of ORs across different studies. Analysis of all 8 studies (n = 1160) included in the meta-analysis showed an increased probability of nephrotoxicity in patients treated with ABLC versus L-AmB (OR, 1.75; RR, 1.55), but there was a significant lack of homogeneity across these studies (p < 0.001). After excluding the study by Wingard et al, the probability of experiencing nephrotoxicity was more similar between the 2 AmB lipid preparations (OR, 1.31; RR, 1.24; n = 916), particularly when the analysis included only the salvage patient population reported by Hachem et al (OR, 1.12; RR, 1.09; n = 839); the 7 remaining studies were more homogenous by Breslow-Day test (p = 0.054). Our results suggest that nephrotoxicity is generally similar for ABLC and L-AmB in patients receiving antifungal therapy and prophylaxis.

Contrast media

IV ContrastVasospasm & ARFRisk factors: DM, myeloma, CRF, dehydration, diuretics, CHFProphylaxis:Hold NSAIDs & diuretics, 24h pre & post contrastIV NS pre & post contrast2 x 600mg PO AcetylcysteineLow dose, low-osmolar contrastAvoid multiple procedures in 48hMonitor renal fxn for 48h

Sodium bicarbonate-based hydration prevents contrast-induced nephropathy: a meta-analysis.

AbstractBACKGROUND: Contrast-induced nephropathy is the leading cause of in-hospital acute renal failure. This side effect of contrast agents leads to increased morbidity, mortality, and health costs. Ensuring adequate hydration prior to contrast exposure is highly effective at preventing this complication, although the optimal hydration strategy to prevent contrast-induced nephropathy still remains an unresolved issue. Former meta-analyses and several recent studies have shown conflicting results regarding the protective effect of sodium bicarbonate. The objective of this study was to assess the effectiveness of normal saline versus sodium bicarbonate for prevention of contrast-induced nephropathy.METHODS: The study searched MEDLINE, EMBASE, Cochrane databases, International Pharmaceutical Abstracts database, ISI Web of Science (until 15 December 2008), and conference proceedings for randomized controlled trials that compared normal saline with sodium bicarbonate-based hydration regimen regarding contrast-induced nephropathy. Random-effects models were used to calculate summary odds ratios.RESULTS: A total of 17 trials including 2,633 subjects were pooled. Pre-procedural hydration with sodium bicarbonate was associated with a significant decrease in the rate of contrast-induced nephropathy (odds ratios 0.52; 95% confidence interval 0.34-0.80, P = 0.003). Number needed to treat to prevent one case of contrast-induced nephropathy was 16 (95% confidence interval 10-34). No significant differences in the rates of post-procedure hemodialysis (P = 0.20) or death (P = 0.53) was observed.CONCLUSION: Sodium bicarbonate-based hydration was found to be superior to normal saline in prevention of contrast-induced nephropathy in this updated meta-analysis.

Innovator and generic cisplatin formulations: comparison of renal toxicity.

To compare the incidence and degree of renal toxicity associated with innovator and generic cisplatin formulations, increase in the serum creatinine (CRN) levels (mg/dL) and incidence of grade 2-3 CRN elevation during the first and all cycles of chemotherapy were retrospectively evaluated in patients treated with innovator (group 1, n = 296) and generic (group 2, n = 321) cisplatin formulations. There were no differences in the sex, age, performance status or number of chemotherapy cycles between groups 1 and 2. The median increases in CRN levels during the first cycle were 0.20 mg/dL regardless of the sex or group. There was no difference in the incidence of grade 2-3 CRN elevation between groups 1 and 2 among female or male patients. The median increases in CRN levels during all cycles were 0.2 (0-1.0) and 0.3 (0-1.8) in the female patients of groups 1 and 2, respectively (P = 0.68), and 0.3 (0-2.1) and 0.5 (0-3.6) in the male patients of groups 1 and 2, respectively (P < 0.001). Grade 2-3 CRN elevation was observed in 18.1% and 24.7% of the female patients in groups 1 and 2, respectively (P = 0.33), and 9.4% and 20.9% of the male patients in groups 1 and 2, respectively (P < 0.001). Renal toxicity was slightly more severe in patients treated with the generic cisplatin formulation than in those treated with the innovator formulation, especially among the male patients.

Case:

A 46-year-old morbidly obese man was admitted to the medical intensive care unit with respiratory failure. He required pressure-control ventilation and high levelsof sedation with continuous-infusion lorazepam. He developed Stenotrophomonas maltophilia pneumonia; treatment included scheduled intravenous trimethoprim-sulfamethoxazole. On day 17 of his hospital course, 3 days after starting the trimethoprim-sulfamethoxazole, the patient developed acute renal failure consistent with acute tubular necrosis. therefore, all drugs were discontinued, and laboratory data were collected. A marked osmol gap, metabolic acidosis, and renal toxicity were attributed .

Propylene glycol is a viscous, colorless liquid solvent used for many drugs with poor aqueous solubility. For many years, propylene glycol has been thought of as safe; however, a review of the literature reveals cases of propylene glycol- associated hyperosmolality, anion gap metabolic acidosis, hemolysis, hyperosmolality, osmol gap, central nervous system depression, arrhythmias, and, although less commonly, renal dysfunction. Several case reports link high doses of intravenous lorazepam with propylene glycol- related toxicities. Other commonly prescribed drugs, including intravenous nitroglycerin, digoxin, phenobarbital, phenytoin, diazepam, trimethoprim-sulfamethoxazole and etomidate, contain large amounts of propylene glycol and have also been associated with toxicity. Laboratory signs of propylene glycol toxicity include hyperosmolality, hyperlactatemia, and osmol gap.

Serum Osmolality 2(Na) + BUN/2.8 + Glucose/18

Anion Gap Na - (CL + HC03)

Osmolar GapCalculated Osmoles= 2(sodium) + urea + glucose= 290-300osmolar gap = calculated - measured osmoles = 0-10

Theoretically, unaccounted osmols may signify a toxic alcohol ingestion.(i.e.. ETOH)( Mannitol, Alcohols, Dye, DMSO, Glycerol, Acetone, Sorbital )

Not sensitive enough to rule out a toxic alcohol ingestion.

Anion GapAG= (sodium) - (bicarbonate + chloride)=12-16

High Anion Gap Metabolic Acidosis

Methanol Uremia Diabetic Ketoacidosis Paraldehyde INH, iron Lactate Ethylene glycol Salicylates Cyanide Alcoholic Ketoacidosis Toluene

The ABGA normal pH and anion gap rules out many ingestions e.g. ASA, cyanide, toxic alcoholIf a patient ingested ETOH and a toxic alcohol, he may not become acidotic until his ETOH is cleared.Consider serial ABGs or toxic alcohol levels

Drug-induce renal structural-functional changesProximal convoluted tubule (s1/s2 segment)AminoglycosideCephaloridineCadmium ClK dichromateRenal vesselNSAIDsACE InhibitorCyclosporin APappillaePhenacetinInterstitiumCephalosporinCadmiumNSAIDsGlomeruliInterferon-GoldPenicillamineProximal straigt tubule (s3 segment)CisplatinMercuric ClDichlorovinyl-L-cysteine

Chronic Interstitial fibrosisLithium,5-aminosalicylic acid, mesalazine, ifosfamideCidofovir, acyclovir, indinavirCyclosporin, tacrolimusUsually progressive, irreversible with interstitail fibrosis, no systemic symptoms

ECSTASY

TREATMENT Hypotension Control: Normal Saline Infusion: 10-20 ml/kg Vasopressor amines( Dopamine, norepinepherine) Cardiac Dysrhythmeia Amidaron, Lidocaine, Atropine Rhabdomyolysios Treatment: Normal Saline Infusion, Diuretic (Mannitol, Furosemide)

ETIOLOGY: post renalBladder obstructioninfectiontumorBPHanticholinergics (diphenydramine, meclizine, benztropine)ganglionic blockers (trimethaphan)

Classification of nephrotoxic drugs by their therapeutic use:

Cardiovascular:ACEIs,CCBs,Mannitol, MethyldopaTriamterene,WarfarinPropranolol,Neuropsychiatric:Amoxapine,CBZ,Li,Pb,Phenytoin,VAImmunosuppresiv:CorticosteroidCyclosporineOKT3Leukocyte A interferonAntimicrobial:Acyclovir,AG,Cephalosporin,CiproAmphotericinB,TCPentamidine,Vanco,TMP,Erythro,PenicillinGastrointestinal:Cimetidine,MagnesiumRanitidinePhosphate enemasDrugs to abuse:AmphetamineCocaineHeroinPhencyclidineRheumatolgic:Acetaminophen,ASAAllopurinol,NSAIDsD-penicillamine,GoldCancer chemotherapy:Carboplatinum,CisplatinMethotrexate,Mithramycin, IL2Nitrosoureas, Miscellaneous:Ascorbic acidGlyburide,LovastatinRadiographic contrast

Overview of mechanisms for renal susceptibility to drug toxicity: Kidney appear more sensitive than other organ to drug toxicity:

Immunologic mechanisms: 1-glomerulonephritides 2-allergic interstitial nephritis(with or without nephrotic syndrome)Nonimmunologic mechanism:

Overview of mechanisms for renal susceptibility to drug toxicity:High blood flow and specialized homodynamic:

Introduction:0.4%,20-25%HTN due to PG,Vasoactive peptide,RASSympathetic nerve systemDrugs:Beta blockers: RBFRadiographic contrast media:shunt RBF Mannitol: GBF due to glomerular feedbackACEIs:dilate glomerular efferent arterioles reduction in GFR

Overview of mechanisms for renal susceptibility to drug toxicity:Tubular epithelia cell absorptive & secretary function:

IntroductionDrugs: Probenecid AG CyclosporinToxic drug may cause cell injury by some mechanisms(impairment of mitocondrial function and decrease ATP synthesis,increase oxidative stress,)

Overview of mechanisms for renal susceptibility to drug toxicity:

Drug metabolism to toxic species: Cytochrome p-450 (in proximal tubular epithelial cells) IN CONTRAST PG and endoperoxide synthetase (renal papilla and medulla)

EXP :Acetaminophen(ATN,Analgesic nephropathy)

Overview of mechanisms for renal susceptibility to drug toxicity:

High energy requirement by renal tubular cells:

Introduction

Amphotericin B

Overview of mechanisms for renal susceptibility to drug toxicity:Concentration of solute in the tubular lumen:Systemic volume depletion increases the percent of water reabsorption in proximal tubule decreases tubular flow increases the concentration of solute and toxins in lumen increases binding of drugs to tubular cellAminoglycoside:nephrotoxicity by systemic volume depletion

Overview of mechanisms for renal susceptibility to drug toxicity:Uric acidification:(Urine PH up to 4.5),(Chemotherapy leads to acute uric acid nephropathy)Increase function of individual nephrons in adoptions to chronic renal insufficiency1-chronic renal insufficiency: injury to some glomerular and tubular unit increases filtering remaining nephrons increases the susceptibility of this nephrons

Radiographic contrast media

Principles for prevention of drug nephropathy Avoid the use of nephrotoxic agents in high risk

When exposure can not be avoided ,specific techniques be used to decrease nephrotoxicity

Hydration ,Oral PG,CCB

Reduction glumerular capillary hydrostatic pressureACEIs RAS deteriorate the glumerular filtration rate

Patient at risk for ACEIs Diagnosis of decrease glumerular filtration rate

Pathogenesis of ACEI nephropathy

Inhibition of prostaglandin dependent renal blood flowNSAIDsPGE2 and prostacyclinPatient at greatest risk for NSAIDsPrevention of NSAIDs induced acute renal failure and NSAIDs nephropathy NSAIDs with ACEIs and cyclosporineCaution and monitoring

Nonspecific renal vasoconstriction:Triamterene Mannitol

CyclosporinPropranolol

Decrease in Clcr +HCTZ+IndomethacinMechanism of cause renalfailure

Decrease RBFMechanism=UnknownNadolol increase RBFMechanismRisk factorTherapyProphylaxisAcute oligoanuric renal failureRisk factors

Increase in vascular permeability:OKT3 Cr

MechanismIncrease in colloid oncotic pressure & bloodviscosity:Dextran-40(IV) alter blood rheologyExogenous erythropoietin increase in blood viscosity

Renal vascular alterationSystemic polyarteritis nodosaPathogenesisDrugs:Methamphetamine,Penicillin,SulfonamidesThrombotic microangiopathy has been described with OCPs,cyclosporine,mitomycin C,cisplatin,quinineNephrotoxicity following long term chemotherapy with mitomycin alone or with some drugs(+5FU,)Microangiopathic hemolytic anemia & thrombocytopeniaRenal failure

Glomerular alterations:Nephrotic syndrome and glomerulonephritisMechanismNephrotic syndrome definitionMinimal change nephrotic syndrome(drug induced,therapy)Focal segmental glomerulosclerosisMembrane nephropathy(most common,immune mediated dx,drugs)Membranoproliferative glomerulonephritisGlomerular amyloidosis(drugs,pathogenesis)

Acute tubular necrosisOne of the most responsible for drug induced renal insufficiencyDrugs:AG,Radiographic contrast media,Cisplatin,AmphotericinSub clinical manifestationMechanism of renal failure in acute tubular necrosis

Aminoglycoside nephrotoxicityDecrease glomerular filtration(5-20%)Initial manifestationPathogenesisThe toxicity of AG in directly proportional to the number of their cationic chargesNeomycin(most)Netilmicin,Streptomycin(least)Gentamicin,Tobramycin(intermediate)Prevention and therapyRisk factors

Radiographic contrast media nephrotoxicityIV common cause of administration hospital-acquired acute renal failureToxicity rangesManifestationMajor risk factors for contrast nephropathyPathogenesisPrevention and therapy:New drugsRe hydrationCCBs,IV Theophylline,Mannitol,Dopamine

Cisplatin nephrotoxicityCause renal tubular damageRisk factorsManifestationMechanismPrevention and treatment:Decrease doses Hypertonic saline Probenecid,GlutathioneMg monitoring,MgCl2

Pentamidine Nephrotoxicity60-90% azotemiaManifestations:Hyperkalemia,metabolic acidosis,HypomagnesemiaToxicity more frequent in AIDsMechanism :UnknownPrevention

Tubulointerstitial disease

Acute allergy interstitial nephritis

Chronic interstitial nephritis

Papillary necrosis:Is common(3-14%ARF)Methicilin,NSAIDs,Cytokine therapy,INF-A,IL-2,LAKTreatmentLi,CyclosporinMild renal insufficiency with long term therapy of Li(10%)Prevention:Avoidance of dehydration and renal monitoringCyclosporine also cause interstitial fibrosis and chronic irreversible insufficiencyPrevention:lessen the doseChronic excessive consumption of combination analgesics containing PhenacetinPhenacetin & Acetaminophen + NSAIDs,DapsonePrevention:Reduce doses,Inh of comb therapy,Hydration

Obstructive nephropathy:

Renal tubular obstruction:Caused by intratubular precipitation of tissue degenerationProducts & drugs Diagnosis:Urine uric acid to Cr ratio>1Prevention and therapy:Hydration,urinary alkalization toPH=7,AllopurinolARF induced by drugs after muscle necrosis andNontraumatic rhabdomyolysis(alcohol,heroin,phencyclidine,Lovastatin,cyclosporine,erythromycin,gemfibrozil,niacin)

External urinary tract obstruction:Drug therapy may leads to urinary tract obstructionElder males with prostate hypertrophy and antich,TCAs,Disopyramide,Antiarrhythmia,CyclophosphamideUse of MESNA

Nephrolithiasis:

Renal calculus formation Sulfdiazine:6% Triamterene-H :1/1500Massive ingestion of magnesium-TrisilicateMagnesium phosphate stones

Laxative abuse

Ammonium urate stones

Patient outcome:Drug induced renal disease is an important clinical problemFor management several guidelines can help :Know the potential nephrotoxicity of diagnostic & therapeutic pharmacologic agents usedCompare the potential risks and expected benefits Consider alternative diagnostic and therapeutic approachesUse the lowest dose and shortest course of therapyMonitorModify 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 describethese pathophysiologicglomerular 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)

AminoglycosidesCephalosporinsCefoxitin CephalothinHydantoin DiureticsMethyldopaCimetidine Trimethoprim

AminoglycosideRisk Factors for Nephrotoxicity?Advanced agePrior renal insufficiencyDehydrationHypokalemia Hypomagnesemia Liver diseaseSepsis

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

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 difficileB) Monobasic and dibasic sodium phosphate (Fleet Phospho-Soda) 45 mL daily as needed for bowel movementC) Diltiazem 10 mg/h for rate control because of atrial fibrillation D) Sodium polystyrene sulfonate (Kayexalate) 30 g orally onceE) All of the above

Prerenal ARF can be exacerbated by the continuation of all of the following medications, except?

A) Lisinopril B) MetolazoneC) 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)

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