Nephrotoxic Drugs

1
Nephrotoxic Drugs
Center for Clinical Pharmacology Department of
Medicine University of Pittsburgh School of
Medicine
Stevan P. Tofovic MD, PhD, FAHA,
FASN tofovic_at_dom.pitt.edu 412-648-3363
2
Nephrotoxic Drugs

• Radiocontrast Agents
• Aminoglycosides
• Nonsteroidal Anti-Inflammatory Drugs (NAIDs)
• Angiotensin-Converting Enzyme Inhibitors (ACEIs)
• Lithium
• Crystal-Induced Acute Renal Failure
• Calcineurin inhibitors (Cyclosporine, Tacrolimus)
• Amphothericin B
• Chemotherapy

3
Nephrotoxic Drugs

• Patient- Related Risk Factors
• Age, Sex
• Previous renal disease
• Diabetes, Multiple myeloma, Lupus, Proteinuric
  disease
• Salt retaining diseases (Chirrosis, Heart Faiure,
  Nephrosis)
• Acidosis, potassium or magnesium depletion
• Hyperuricemia, Hyperuricosuria
• Kidney transplant

4
Nephrotoxic Drugs

• Drug - Related Risk Factors
• Inherent nephrotoxic effects
• Dose
• Duration, frequency and form of administration
• Repeated exposure
• Drug interaction (synergistic toxic effects)

5
Radiocontrast Agents

• Ionic vs. Nonionic
• High (1500-1800)
• Low (600-850)
• Iso-osmolal ( 290 mOsm/kg))
• Plasma 285 mOsm/kg
• CSF 310 mOsm/kg

6
Radiocontrast Agents

• First generation - Ionic monomers, hyperosmolal
  Diatrizoate, Iothalamate
• Second generation Nonionic monomers, lower
• osmolality
• Iopamidol, Iohexol, Iopromide, Ioversol
• Newest agents Nonionic dimers, iso-osmolal
  Iodixanol

7
Radiocontrast Agents

• Pathogenesis
• Renal Vasoconstriction
• (Adenosine, Endothelin)
• Tubular Injury
• Oxidative stress induced damage

8
Adenosine and Tubuloglomerular Feedback
JGC
Vasoconstriction
Renin release
A1
Adenosine
TGF
MD
MD - Macula Densa TGF - Tubuloglomerular
Feed-back
PGC GFR
A2
JGC - Juxtaglomerular Cells
Vasodilatation
9
Radiocontrast Agents

• Risk Factors
• Underlying renal disease (Cr gt1.5mg/dL)
• Diabetic nephropathy, Heart Failure, i.e.
  Hypovolemia
• Multiple Myeloma
• Dose (lower doses safer but not necessarily safe)

10
Radiocontrast Agents

• Incidence
• Negligible when renal function is normal (even if
  diabetic)
• 4 -11 in patients with Cr 1.5 4.0 mg/dL
• 50 if Cr gt 4.0 mg/dL and in diabetic
  nephropathy
• Diagnosis
• Characteristic rise in plasma Cr following
  administration of the agent

11
Radiocontrast Agents

• Therapy
• Hydratation v Mannitol ? Diuretics ?
• Acetylcystein, theophyllin, calcium channel
  blockers
• Prevention
• Use of alternative diagnostic procedures in high
  risk
• patients
• Avoidance of volume deletion or other
  nephrotoxins
• Low-doses of low- or iso-somolar agent
• IV saline or acetylcysteine

12
Aminoglycosides
Amikacin AMIKIN Gentamicin GARAMYCIN
Neomicin Netilmicin NETROMYCIN
Kanamicin KANTREX Streptomycin Tobramycin
TOBREX, NEBCIN
13
Aminoglycosides

• Patient- Related Risk Factors
• Age
• Previous renal disease
• Dehydratation, Volume depletion
• Potassium or magnesium depletion
• Liver Disease (renal hypoperfusion)
• Sepsis ( endotixuns, volume depletion, renal
  hypo- perfusion)

14
Aminoglycosides

• Drug - Related Risk Factors
• Inherent nephrotoxic effects
• Gentamicin gt Amikicin Tombamycin
• Prolonged high trough levels (gt 2.0 ng/ml)
• Dose Duration Frequency
• Single daily dose Post-antibiotic effect
• Drug interaction Cephalothin Cyclosporin A
• Cisplatin, Cephalosporins, NSAIDs, ACEIs,
• Diuretics

15
Aminoglycosides

• Pathogenesis
• Number of cationic amino groups
• Bind at negatively charged sites at brush border
  membrane of proximal tubules
• More distal segments may be also affected
  (polyuria, hypomagnesemia)
• Incidence
• In 10-20 of patients increase in plasma Cr of
  0.5-1 mg/dL

16
Aminoglycosides

• Diagnosis- Clinical Course
• Change in baseline creatinine (day 3-5)
• Nonoliguric acute renal failure
• Enzymuria, tubular proteinuria Urine sediment
  may show granular and epithelial cell cats
• Prevention Therapy
• General rules of prevention of nephrotoxicity
• Discontinuation of the treatment
• Supportive therapy fluid and electrolytes
  balance

17
Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)

• Chemical Structure / Activity Generic Name
• __________________________________________________
  ______
• Acetic acids Diclofenac, Indomethacin,
  Sulindac,
• Fenamates Meclofenamate, Mefenamic acid
• Napthylalkanones Nabumetone
• Oxicams Meloxicam and Piroxicam
• Propionic acids Fenoprofen, Flurbiprofen,
  Ibuprofen, Ketoprofen, Naproxen, Oxaprozin
• Pyranocaboxylic acid Etodolac
• Pyrrolizine carboxylic acid Ketorolac
• Selective COX-2 inhibitors Celecoxib,
  Rofecoxib, Valdecoxib,

18
Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)

• Hemodynamically- Induced ARF
• Acute Interstitial Nephropathy Proteinuria
• Papillary necrosis and chronic renal failure
  (Analgesic nephropathy)
• Salt and water retention Hyperkalemia
  Hypertension

19
Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)

• Hemodynamycally- Induced ARF
• Inhibition of prostaglandins synthesis
• Renal prostaglandins are primarily vasodilators
• NSAIDs do not impair renal perfusion in normal
  subjects
• Patients at risk Preexisting renal disease
  (glomerular disease nephrotic syndrome ,lupus)
  Hypercalcemia Congestive Heart Failure,
  Cirrhosis, Volume depletion (vomiting, diarrhea,
  diuretics)

20
Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)

• Hemodynamycally- Induced ARF (Contd)
• Mild to moderate oliguric ARF that begins within
  several days after initiation of treatment
• Hyperkalemia unproportional to the renal failure,
  and low fractional excretion of sodium.
• If recognized early, reversible after
  discontinuation of NSAID.

21
Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)

• Acute Interstitial Nephropathy Proteinuria
• Prolonged use of NAIDs (elderly women)
• Acute interstitial nephritis
• Minimal-change glomerular disease
• Proteinuria
• No evidence of allergic hypersensitivity T-cell
  infiltration EM fusion of epithelial foot
  processes
• Prognosis good after discontinuation of therapy
  Corticosteroids ?

22
Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)

• Analgesic nephropathy (Papillary necrosis and
  chronic renal failure) Acetaminophen Tylenol
  Ibuprofen Advil, Motrin Aspirin, Naproxen
• Pre- vs. Post-Phenacetin-Era
• Single vs. combined analgesics
• Nephrotoxicity is cumulative dose-dependent (
  2-3 pounds 3 pills/day for several years)
• Patients with history of depended behaviors

23
Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)

• Analgesic nephropathy (Papillary necrosis and
  chronic renal failure) contd
• Phenacetin is converted to acetaminophen
• Renal risk of chronic acetaminophen monotherapy
  is unknown
• Aspirin alone not toxic, but potentiates the
  effects of phenacetin and acetaminophen
• The effects of long-term use of COX-2 inhibitors
  is unknown

24
Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)

• Analgesic nephropathy (Papillary necrosis and
  chronic renal failure) contd
• Pathogenesis
• Renal damage mainly in the medulla
• Initially thickening of the vasa recta patchy
  areas of tubular necrosis later papillary
  necrosis
• Slowly progressive GRF Asymptomatic, sometimes
  hematuria, flank pain, or urinary infections.

25
Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)

• Analgesic nephropathy
• Excessive consumption of analgesics 100
• Women 80
• Headache 80
• GI disturbance 35
• Urinary Tract Infections 40
• Papillary necrosis (clinical) 20
• Papillary calcification 65

26
Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)

• Papillary necrosis

27
Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)

• Papillary necrosis

28
Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)

• Salt and water retention Renal PGs also may
  have a natriuretic effect, and antagonize the
  effects of ADH
• Not important it the basal state, but may
  be significant when there is
  neurohumoral activation/volume depletion
• Hyperkalemia Renal PGs inhibits renin release
• (Hyporeninemic-hypoaldosteronism-induced
  K
• Hypertension Renal PGs also may lower systemic
  vascular resistance.
• May reduced the effects of
  antihypertensive drugs

29
ACE Inhibitors-Induced Acute Renal Failure

• First group of antihypertensive drugs shown to be
  renoprotective
• High renin patients are at risk
• Bilateral (gt70) renal artery stenosis
• Moderate to Severe congestive hart failure
• Volume deleted (excessive use of diuretics)

30
Control of Renin Secretion
ACE Inhibitors-Induced Acute Renal Failure

• Macula densa pathway Inhibition of Na
  reabsorption ? ? Na delivery to the macula
  densa ? ? renin secretion
• Intrarenal baroreceptor pathway ? BP/ Renal
  hypoperfusion ? ? intrarenal baroreceptor activty
  ? ? renin secretion
• Beta-adrenergic receptor pathway? Sympahtetic
  activity (i.e., BP ?) ? activation of b1
  receptors ? ? renin secretion

31
ACE Inhibitors-Induced Acute Renal Failure
INTRAGLOMERULAR PRESSURE
Angiotensin II
Angiotensin II
Arterial pressure



Afferent arteriole
Efferent arteriole
20 mmHg
Bowmans capsule
32
Renin Angiotensin System and Efferent
Arteriolar Constriction
Renal ischemia Renin release Angiotensin II
formation Efferent arteriolar constriction Incre
ased intraglomerular pressure Maintained renal
function
33
ACE Inhibitors and Efferent Arteriolar
Constriction
Renal ischemia Renin release ? Angiotensin II
formation Efferent arteriolar dilation Reduced
intraglomerular pressure Reduced GFR
Warnings for use of ACEIs !!!
34
CONGESTIVE HEART FAILURE
Angiotensinogen
renin
diuretics b- adrenergic stimulation
AngI
ACEIs
X
Low blood pressure
poor renal perfusion sodium depletition
AngII


Afferent arteriole
Efferent arteriole
Maintenance of GFR at low rate
ACEIs may cause renal failure
35
Calcineurin Inhibitors

• Cyclosporin A SANDIMMUNE,
• NEORAL Tracolimus PRO-GRAF
• Mechanism or action
• Cyclosporin vs Tracolimus

36
Calcineurin Inhibitors

• Acute nephrotoxicity
• Azotemia renal vasoconstriction, reduced RBF and
  GFR Oliguric ATN with high doses
• Relatively more dose-dependent
• Largely reversible Calcium channel
• blockers (/-)
• Difficult to differentiate from acute rejection
• (renal biopsy)

37
Calcineurin Inhibitors

• Chronic nephrotoxicity
• Factors responsible for chronic nephrotoxicity
  are not well understood.
• Relatively less dose-dependent
• Sustained renal vasoconstriction/renal ischemia
  Renin-Angiotensin System
• Cyclosporineinduced hypertension

38
Calcineurin Inhibitors
Chronic nephrotoxicity

• obliterative arteriolopathy
• vacuolization of the tubules
• focal areas of tubular atrophy
• interstitial fibrosis

39
Crystal-Induced ARF

• Acyclovir (antiviral agent )
• Indinavir (antiretroviral agent, protease
  inhibitor)
• Methotrexate (antineoplastic agent,
  antimetabolite)
• Sulfonamide antibiotics
• Triamterene

40
Crystal-Induced ARF
Sulfonamide crystals
Indinavir sulfate urinary crystals Gagnon et al.
1998, Ann Intern Med 128-321
41
Amphothericin B

• Used for the treatment of often life-threatening
  fungal infections.
• Tubular injury and renal vasoconstriction
  proposed to have an important role in
  pathogenesis
• Drop in GFR mediated at least in part via TGF
  mechanisms
• Volume expansion (salt loading) may reduces drop
  in GFR but not tubular toxicity
• Usually reversible with discontinuation of
  therapy
• The new liposomal (phospholipid vesicles)
  preparations seem to be less toxic

42
Nephrotoxic Drugs

• Prevention General Rules
• Be aware of nephrotoxic potential of specific
  drugs
• Identify patients at risk
• Be aware of increased risk in elderly
• Asses the benefit/risk ratio for Rx of
  potentially nephrotoxic drug

43
Nephrotoxic Drugs

• Prevention General Rules (Contd)
• Avoid dehydration/Be aware of volume depletion
• Limit dose and duration of treatment
• Adjust the dose based on changes in GFR
• Avoid a combination of potentially nephrotoxic
  drugs