Drug induced nephrotoxicity

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Drug induced nephrotoxicity

• Naser Hadavand

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(No Transcript)
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Classification of Drug Induced Disordres

• Definitions
• Type
• Onset
• Severity

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Definition and Classifications of Adverse
Reaction Terms

• Adverse Event
• Adverse Drug Reaction
• Side Effect

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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.

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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.

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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.

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• Examples

• Adverse Event
• Adverse Drug Reaction
• Side Effect

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

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Classification

• Definitions
• Type
• Onset
• Severity

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Comparison Type A and Type B

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Adverse Drug Reactions

• Unwanted 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.

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Introduction
Drug induced nephrotoxicity

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

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Incidence

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  ?????? ?? ???? ?? ???.

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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)

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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.

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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

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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)

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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

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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 1999l246247-52 TDM 19879161-5)

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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.

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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 BUN
• Urinary findings Eosinophiluria, Isosthenuria,
  hematuria, Sterile pyuria white blood cells and
  no bacteria

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Acute interstitial nephritis

• Symptoms and Signs
• Classic triad (Methicillin induced
  hypersensitivity)
• Low grade fever (gt70 of cases)
• Rash (gt30 of cases)
• Arthralgia (gt15 of cases)
• Acute Renal Failure
• Oliguria
• Malaise
• Nausea or Vomiting
• Labs General
• Urinalysis
• Eosinophiluria
• Proteinuria
• Fractional Excretion of Sodium gt1
• Renal Function tests with renal insufficiency
• Cr BUN increased
• Miscellaneous
• Hyperchloremic Metabolic Acidosis

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Acute interstitial nephritis

• Causes
• Infection
• Diphtheria , Group A beta hemolytic Streptococcus
  (classic)
• Legionella , Yersinia , Staphylococcus or
  Streptococcus infection
• Mycobacterium , Toxoplasmosis , Mycoplasma ,
  Leptospira
• Rickettsia , Syphilis , Herpes viruses (e.g. CMV,
  EBV, HSV)
• Human Immunodeficiency Virus (HIV),Hantavirus
• Hepatitis C , Mumps
• Medications (AIN occurs gt2 weeks after drug
  started)
• Penicillins and Cephalosporins
• Hypersensitivity (fever, rash, arthralgia)
• Sulfonamides
• Vasculitis reaction
• NSAIDs
• Nephrotic Syndrome type reaction
• Rifampin , Diuretics (Thiazides and Lasix),
  Allopurinol , Cimetidine , Ciprofloxacin
• Dilantin
• Other medications have caused AIN to a lesser
  extent
• Miscellaneous conditions

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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.

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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.

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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.

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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.

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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,lt25g/L, because some of the
  protein albumin has gone from the blood to the
  urine) but not large enough to allow cells
  through (hence no haematuria). By contrast, in
  nephritic syndrome red blood cells pass through
  the pores, causing haematuria.

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Diagnosis
Nephrotic Syndrom
Pro

• Proteinuria gt3.5g/d
• Hypoalbuminemia SAlb lt30g/L
• Edema
• Hyperlipidemia.

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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.

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CLASSIFICATIONS

• Anuric lt 50ml/day urine output
• Oliguric 50-400ml/day urine output
• Non-oliguric gt400ml/day urine output

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Urine Analysis
Urinalysis (complete) (urine) Appearance clear, yellow.Specific gravity 1.001 - 1.035pH 4.6 - 8.0Protein negativeGlucose negativeKetones negativeBilirubin negativeOccult blood negativeWBC esterase negativeNitrite negativeWBC lt/ 5 high-power fieldRBC lt/ 3 high-power fieldRenal epithelial cells lt/ 3 /high-power fieldSquamous epithelial cells None or few/high-power fieldCasts noneBacteria noneYeast none
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Kidney Function Tests
Urea Nitrogen blood (BUN) (serum) 7 - 30 mg/dLAlternative source 8-25 mg/dL 2.5 - 10.7 mmol urea /LAlternative source 2.9-8.9 mmol/L
Creatinine (Serum) 0.7 - 1.4 mg/dl (lt1.2) lt/ 106 µmol/L
Creatinine (Urine) Male 0.8 - 2.4 g/dayFemale 0.6 - 1.8 g/day Male 7.1 - 21.2 mmol/dayFemale 5.3 - 15.9 mmol/day
Creatinine Clearance (CrCL)Note Creatinine clearance reference intervals are based on a body surface area of 1.73 square meters. Male lt12 yr 50-90 mL/minute, gt12 yr 97-137 mL/minute Female lt 12 yr 50-90 mL/minute, gt 12 yr 88-128 mL/minute
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• ??????? ?????
• Pre Renal ? BUN/ ? Cr gt20
• Post Renal ? BUN/ ? Cr 10 20
• Renal ? BUN/ ? Cr lt 10

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Kidney Function Tests
PaCO2Normal 35 - 45 mmHg (4.6 - 6 kPa)Respiratory acidosis gt 45 mmHg (gt 6 kPa)Respiratory alkalosis lt35 mmHg (lt 4.6 kPa)
BE (Base Excess)--------------------------Normal -2 to 2 mmol/LMetabolic acidosis lt -2 mmol/L
Mild -4 to -6
Moderate -6 to -9
Marked -9 to -13
Severe to lt -13 Metabolic alkalosis gt 2 mmol/L
Severe gt 13
Marked 9 to 13
Moderate 6 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.
HCO3---------------------------Normal 22 - 26 mEq/LMetabolic acidosis lt22 mEq/LMetabolic alkalosis gt 26 mEq/LStandard Bicarbonate Calculated value. Similar to the base excess. It is defined as the calculated bicarbonate concentration of the sample corrected to a PCO2 of 5.3kPa (40mmHg).
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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)
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ESTIMATION OF RENAL FUNCTION

• Cockcroft and Gault Equation
• Estimates renal function when creatinine levels
  are at steady-state
• not usually the case in acute renal failure

CLCr(ml/min) (140-Age)(Wt.)
72(Scr)
0.85 (female)
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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

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• 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 gt65yo and
  creatininelt1, use 1 to calculate the creatinine
  clearance.

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• 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)

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Normal Blood Gases Normal Blood Gases Normal Blood Gases
Arterial Venous
pH 7.35 - 7.45 7.32 - 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. 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. 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.
PaO2 80 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) 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) 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. The calculated value of the amount of bicarbonate in the bloodstream. Not a blood gas but the anion of carbonic acid. The calculated value of the amount of bicarbonate in the bloodstream. Not a blood gas but the anion of carbonic acid.
PaCO2 35-45 mm Hg 38-52 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 lt--- --gt H HCO3 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 lt--- --gt H HCO3 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 lt--- --gt H HCO3
B.E. 2 to 2 mEq/literOther 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 equationBase excess 0.93 (HCO3 - 24.4 14.8(pH - 7.4))Alternatively Base excess 0.93HCO3 13.77pH - 124.58A base excess gt 3 metabolic alkalosis a base excess lt -3 metabolic acidosis 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 equationBase excess 0.93 (HCO3 - 24.4 14.8(pH - 7.4))Alternatively Base excess 0.93HCO3 13.77pH - 124.58A base excess gt 3 metabolic alkalosis a base excess lt -3 metabolic acidosis 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 equationBase excess 0.93 (HCO3 - 24.4 14.8(pH - 7.4))Alternatively Base excess 0.93HCO3 13.77pH - 124.58A base excess gt 3 metabolic alkalosis a base excess lt -3 metabolic acidosis
SaO2 95 to 100 50 - 70
The arterial oxygen saturation. The arterial oxygen saturation. The arterial oxygen saturation.
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?? ??????? ???? ??????

• Definitions
• Type
• Onset
• Severity

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?????? ??? ???? ????? ???? ?? ????? ?? ????? ????
45
??? ????? ????? NSAIDs ?? ?????? ????? ????
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??? ??? ? ??? ???? ?? ??????? ??? ????? ?????
??? ???? ?????? ????? ?? ???? ??? ?? ?? ?????
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?????? ?? ????? ????? ???? ?? ?????? ?????? ??
??? ???? ?????

• Acute interstitial nephritis
• Acute Tubular Necrosis
• Obstructive

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Aminoglycosides

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

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??? ?????????? ???? ?? ????? ?? ???? ????? ?????
??? ????? ?????
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Amphotericin B

• Are Liposomal formulations affect
  nephrotoxicity

51
????? ???????? ??????? ????? ???? ?? ???? ?? ????
??????? ???? ??/ ????? ?? ????

• ?????
• ?? ????

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?? ????? ??????? ???? ????? ACEI ?????? ????????
?? ?? ????

• ????
• ??????

53
?? ????? ??????? ???? ????? ACEI ?????? ????????
?? ?? ????

• ????
• ??????

54
??? ?? ?????? ???????? ?? ??????? ???? ?????
ACEI ???? ???? ??? ?????

• ???
• ???
• ????? ????

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????? ????? ?? ?????? ?? ??????? ??? ????? ?? ??
????

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

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(No Transcript)
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???? ??????? ?? ????? ??????? ? ???? ?????? ??
????? ?? ???? ??? pH ????? ????? ???? ?? ?????

• ?????
• ????
• ????? ????

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???? ????? ?? ???? ??????? ????? ????? ?????
?????? ?????? ????

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

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?? ?????? ?? ????? ??? ???? ???? ??? ?????

• Relative Serum Creatinine increase 50 over
  baseline
• Absolute Serum Creatinine increase
• Serum Creatinine baseline lt2 mg/dl Creatinine
  increase 0.5 mg/dl over baseline
• Serum Creatinine baseline gt2 mg/dl Creatinine
  increase 1.0 mg/dl over baseline

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(No Transcript)
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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)

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DRUG-INDUCED RENAL FAILURE
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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

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???

• ???? ??? ??? ?????????
• ??????? ?? ?????? ??? ?????????(NSAIDs)
• ??????????
• ???? ??? ?????????
• ??????????? ???
• ???????? ??? ????

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History
1

• The 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.

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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.

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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.

68
History
3

• In 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.

69
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.

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71
???? ??????? ?????
Aspirin Celecoxib
Diclofenac Indomethacin
Ibuprofen Ketorolac
Mefenamic acid Naproxen
Sulindac Salicylic acid
Piroxicam Tolmetin
Sodium salicylate Indomethacin
Naproxen
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74
GCS
Classical NSAIDs

• Endothelium, brain, spinal cord

N.B. COX-2 also in

• Kidney (Macula densa), ovaries, uterus

75
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.

76
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.

77
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.

78
Drug interactions

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

79
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

80
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.
• NSAIDs are generally indicated for the
  symptomatic relief of the following conditions
• Rheumatoid arthritis
  Osteoarthritis
• Inflammatory arthropathies (e.g. ankylosing
  spondylitis, psoriatic arthritis, Reiter's
  syndrome)
• Acute gout
  Dysmenorrhoea (menstrual pain)
• Metastatic bone pain
  Headache and migraine
• Postoperative pain
• Mild-to-moderate pain due to inflammation and
  tissue injury
• Muscle stiffness and pain due to Parkinson's
  disease
• Pyrexia (fever) Ileus
  Renal colic
  
• Ductus arteriosus is not closed within 24 hours
  of birth
• 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 A2.

81
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

82
????? ?????NSAIDs

• ????? ?????
• ???? 10-1
• ?????? ???? NSAIDs ?? ??????? ?? ??????? ????? ?
  ???? ??????? ??????? ?????????? ??????
  ??????????? (????????? ?????????) ? ???? ?????
  ??? ACE (?????????? ?????????)
• ???? ?? ??? ???????? ?? ??????? ??? ? ???????
  ???? ??????? ?????

83
NSAIDs/COXibs

• 5 ??????? ???? ????? NSAIDs ?? ??? ???? ???????
  ??? ????? ?? ????. ?? ???? ????? ?? ????????? ??
  ?????? ??? ??? ????? ?? ???.

84
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

85
?? ??? ?? ?? ??? ???? NSAIDs ?????? ????? ???? ??
???? ????? ?? ?????

• ?? ????
• ?? ????
• ?? ???
• ?? ???
• ?? ???
• ????? ???? ??? ????

86
???? NSAIDs ?????? ????? ????? ????? ?? ?????
87
???? NSAIDs ?????? ????? ????? ????? ?? ?????

• Sulindac
• Naproxen

88
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.
• - 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.

89
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.
• - 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.

90
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

91
Analgesic nephropathy

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

92
Analgesic nephropathy

• Signs and tests
• A physical examination may show signs of
  interstitial nephritis or kidney 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.
• Tests that may be done include
• - CBC
• - sedimentation in the urine
• - Intravenous pyelogram(IVP)
• - Toxicology screen
• - Urinalysis

93
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.
• 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.

94
Analgesic nephropathy

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

95
Drug-Induced Acute Renal Dysfunction

• Acute Renal Failure
• - Prerenal
• NSAIDs, CyA/Tacrolimus, ACEI/ARB,
  Diuretics

96
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

97
??? ?????? ????? ????? ???? ?? ??????????? ?? ??
????? ?????

• BUN/Cr
• Angiography
• Biopsy

98
Drug-Induced Acute Renal Dysfunction

• Acute Renal Failure
• - Prerenal
• NSAIDs, CyA/Tacrolimus, ACEI/ARB,
  Diuretics

99
Side Effects
100
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 gt2.5
  mg/dL or 221 µmol/L) or hyperkalaemia (K gt5.0
  mmol/L)
• Symptomatic or severe asymptomatic hypotension
  (SBP lt90 mmHg)
• Drug interactions to look out for
• K supplements/ K sparing diuretics (including
  spironolactone)
• NSAIDs
  avoid unless essential
• AT1-receptor blockers

101
Drug induced renal structural functional
alteration

• Increase in BUN and Cr without a decrease in GFR
• Increase in BUN and Crnorm
• Corticosteroid,TC(these increase protein
  catabolism
• Increase in Cr,BUNnorm
• TMP,Pyrimethamine,Cimetidine

• Psuedo renal failure
• Hemodynamically mediated renal failure
• Renal vascular alterations
• Glomerular alteration
• Acute tubular necrosis
• Tubulointerstitial disease
• Obstructive nephropathy
• Nephrolithiasis

• Reduction glumerular capillary hydrostatic
  pressure
• Inhibition of prostaglandin-dependant renal blood
  flow
• Nonspecific renal vasocons
• Increase vascular permeability
• Increase in colloid oncotic pressure

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103
Afferent Arteriolar vasoconstrictors

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

104
Efferent Arteriolar vasodilators

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

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106
Acute Renal FailurePRE-RENAL

• ACEI/ARB
• NSAIDs
• Diuretics
• Immunosuppressives (CyA, Tacrolimus)

107
Acute Renal FailurePRE-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

108
ACE Inhibitors ARBs

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

109
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

110
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

111
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 µmol/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

112
Putting Guidelines into Practice ACE
INHIBITORS

• ACE Inhibitors Problem Solving (continued)
• Worsening renal function (cont.)
• If K rises to gt6.0 mmol/L, or creatinine
  increases by gt100 or to above 4 mg/dL (354
  µmol/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

113
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

114
?? ???? ?? ????? ????? ???? ACEIs ??????????
????? ?? ?????????????
115
?? ???? ?? ????? ????? ???? ACEIs ??????????
????? ?? ?????????????

• ?? ?????? ?? ?? ??????? ??? ?? ???? ?? ???? ????
  ???????? ??? ???????????? ?????.

116
ACEIs - Additional Considerations

• Compelling 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

117
Angiotensin Receptor Blocker Mechanism of Action
Renin
Angiotensinogen
Angiotensin I
ACE
AT II Receptor Blocker
Other Pathways
Angiotensin II
AT I Receptor Blocker
Receptors
ATII
ATI
Antiproliferative Action
Vasodilation
Proliferative Action
Vasoconstriction
118
Angiotensin II Receptor Antagonists

• Candesartan (Atacand)
• Eprosartan (Tevetan)
• Irbesartan (Avapro)
• Losartan (Cozaar)
• Olmesartan (Benicar)
• Telmisartan (Micardis)
• Valsartan (Diovan)

119
Angiotensin II Receptor Antagonists
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
Losartan Potassium 25 mg TABLET ORAL -
Losartan Potassium 50 mg TABLET ORAL -
Losartan Potassium/Hydrochlorothiazide 50/12.5 mg TABLET ORAL ( Losartan Potassium 50mg Hydrochlorothiazide 12.5mg)
Eprosartan 300 mg Tablet ORAL
Eprosartan 600 mg Tablet ORAL
120
Renin Angiotensin Aldosterone
Drug Initial Dose Max Single Dose
ACE- inhibitors ACE- inhibitors 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 Angiotensin Receptor Blocker 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 Aldosterone Antagonists Aldosterone Antagonists
Spironolactone 12.5 to 25 mg 25 mg once or twice
Eplerenone 25 mg once 50 mg once
121
Drug-Induced Acute Renal Dysfunction

• Acute Renal Failure
• - Prerenal
• NSAIDs, CyA/Tacrolimus, ACEI/ARB,
  Diuretics

122
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

123
Acute interstitial nephritis

• Causes
• Medications (AIN occurs gt2 weeks after drug
  started)
• Penicillins and Cephalosporins
• Hypersensitivity (fever, rash, arthralgia)
• Sulfonamides
• Vasculitis reaction
• NSAIDs
• Nephrotic Syndrome type reaction
• Rifampin , Diuretics (Thiazides and Lasix),
  Allopurinol , Cimetidine , Ciprofloxacin
• Dilantin
• Other medications have caused AIN to a lesser
  extent
• Miscellaneous conditions
• Glomerulonephritis , Necrotizing Vasculitis,
  Systemic Lupus Erythematosus
• Acute kidney transplant rejection

124
Acute interstitial nephritis

• Causes
• Infection
• Diphtheria , Group A beta hemolytic Streptococcus
  (classic)
• Legionella , Yersinia , Staphylococcus or
  Streptococcus infection
• Mycobacterium , Toxoplasmosis , Mycoplasma ,
  Leptospira
• Rickettsia , Syphilis , Herpes viruses (e.g. CMV,
  EBV, HSV)
• Human Immunodeficiency Virus (HIV),Hantavirus
• Hepatitis C , Mumps
• Medications (AIN occurs gt2 weeks after drug
  started)
• Penicillins and Cephalosporins
• Hypersensitivity (fever, rash, arthralgia)
• Sulfonamides
• Vasculitis reaction
• NSAIDs
• Nephrotic Syndrome type reaction
• Rifampin , Diuretics (Thiazides and Lasix),
  Allopurinol , Cimetidine , Ciprofloxacin
• Dilantin
• Other medications have caused AIN to a lesser
  extent
• Miscellaneous conditions

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127
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

128
AminoglycosidesSerum concentration - Sampling

• G T
• Peak 5-8 mcg/ml
• Trough less 2 mcg/ml
• A
• Peak 20-30 mcg/ml
• Trough less 10 mcg/ml
• V
• Peak 15-30 mcg/ml
• Trough less 5-20 mcg/ml
• Infusion time G A 30 min, V 60 min(less
  1250 mg) , 90 min(more 1250 mg)

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130
Antibiotics

• Aminoglycosides
• Trough gt2mg/L, repeated course in months ?
  nonoliguric ATN
• Recommendations
• hi OD dose (5-7mg/kg/24h x 2-3wks) is less
  nephrotoxic and equally effective
• Follow levels, correct K
• CrCl gt 60, 1-2.5mg/kg Q8H
• CrCl 40-60, Q12H