Title: Nephrotoxic Drugs
1Nephrotoxic 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
2Nephrotoxic 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
3Nephrotoxic 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
4Nephrotoxic Drugs
- Drug - Related Risk Factors
- Inherent nephrotoxic effects
- Dose
- Duration, frequency and form of administration
- Repeated exposure
- Drug interaction (synergistic toxic effects)
5Radiocontrast Agents
- Ionic vs. Nonionic
- High (1500-1800)
- Low (600-850)
- Iso-osmolal ( 290 mOsm/kg))
- Plasma 285 mOsm/kg
- CSF 310 mOsm/kg
6Radiocontrast 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
7Radiocontrast Agents
- Pathogenesis
- Renal Vasoconstriction
- (Adenosine, Endothelin)
- Tubular Injury
- Oxidative stress induced damage
8Adenosine 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
9Radiocontrast 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)
10Radiocontrast 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 -
11Radiocontrast 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
12Aminoglycosides
Amikacin AMIKIN Gentamicin GARAMYCIN
Neomicin Netilmicin NETROMYCIN
Kanamicin KANTREX Streptomycin Tobramycin
TOBREX, NEBCIN
13Aminoglycosides
- 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)
14Aminoglycosides
- 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
15Aminoglycosides
- 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
16Aminoglycosides
- 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
17Nonsteroidal 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,
18Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)
- Hemodynamically- Induced ARF
- Acute Interstitial Nephropathy Proteinuria
- Papillary necrosis and chronic renal failure
(Analgesic nephropathy) - Salt and water retention Hyperkalemia
Hypertension
19Nonsteroidal 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)
20Nonsteroidal 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.
21Nonsteroidal 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 ?
22Nonsteroidal 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
23Nonsteroidal 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
24Nonsteroidal 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.
25Nonsteroidal 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
26Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)
27Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)
28Nonsteroidal 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
29ACE 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)
30Control 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
31ACE 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 !!!
34CONGESTIVE 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
35Calcineurin Inhibitors
- Cyclosporin A SANDIMMUNE,
- NEORAL Tracolimus PRO-GRAF
- Mechanism or action
- Cyclosporin vs Tracolimus
36Calcineurin 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)
37Calcineurin 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
38Calcineurin Inhibitors
Chronic nephrotoxicity
- obliterative arteriolopathy
- vacuolization of the tubules
- focal areas of tubular atrophy
- interstitial fibrosis
39Crystal-Induced ARF
- Acyclovir (antiviral agent )
- Indinavir (antiretroviral agent, protease
inhibitor) - Methotrexate (antineoplastic agent,
antimetabolite) - Sulfonamide antibiotics
- Triamterene
40Crystal-Induced ARF
Sulfonamide crystals
Indinavir sulfate urinary crystals Gagnon et al.
1998, Ann Intern Med 128-321
41Amphothericin 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
42Nephrotoxic 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
43Nephrotoxic 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