Obat-obat nefrotoksik

Em sutrisna
 Golongan obat nefrotoksik
 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
 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
 Drug - Related Risk Factors
•

 Inherent nephrotoxic effects

 Dose
 Duration, frequency and form of
administration
 Repeated exposure
 Drug interaction (synergistic toxic
effects)
 Radiocontrast Agents

 Ionic vs. Nonionic

 High (1500-1800)
Low (600-850)
Iso-osmolal (~ 290 mOsm/kg))

 Plasma: 285 mOsm/kg

CSF: 310 mOsm/kg
 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
 Pathogenesis:

 Renal Vasoconstriction
(Adenosine, Endothelin)

 Tubular Injury
Oxidative stress induced damage
Adenosine and Tubuloglomerular Feedback
JGC Vasoconstriction
Renin release A1

Adenosine TGF

MD - Macula Densa
MD
TGF - Tubuloglomerular PGC
Feed-back A2
JGC - Juxtaglomerular Cells GFR
Vasodilatation
 Risk Factors:

 Underlying renal disease (Cr >1.5mg/dL)

 Diabetic nephropathy, Heart Failure, i.e.
Hypovolemia
 Multiple Myeloma

 Dose (lower doses safer but not

necessarily safe)
 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 > 4.0 mg/dL and in diabetic nephropathy

 Diagnosis
 Characteristic rise in plasma Cr following
administration of the agent
 Radiocontrast Agents
 Therapy:
Hydratation √ ; 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
Aminoglycosides

Amikacin [AMIKIN ®]
Gentamicin [GARAMYCIN ®]
Neomicin
Netilmicin [NETROMYCIN ®]
Kanamicin [KANTREX ®]
Streptomycin
Tobramycin [TOBREX, NEBCIN ®]
 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)
 Aminoglycosides
Drug - Related Risk Factors
 Inherent nephrotoxic effects
Gentamicin > Amikicin & Tombamycin

 Prolonged high trough levels (> 2.0 ng/ml)

 Dose; Duration; Frequency

Single daily dose; “Post-antibiotic” effect

 Drug interaction: Cephalothin Cyclosporin A;

Cisplatin, Cephalosporins, NSAIDs, ACEIs,
Diuretics
 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
 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
Nonsteroidal Anti-Inflammatory
Drugs (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,

Nonsteroidal Anti-Inflammatory
Drugs (NSAIDs)
 Hemodynamically- Induced ARF

 Acute Interstitial Nephropathy + Proteinuria

 Papillary necrosis and chronic renal failure

(Analgesic nephropathy)

 Salt and water retention; Hyperkalemia;

Hypertension
Nonsteroidal Anti-Inflammatory
Drugs (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)
Nonsteroidal Anti-Inflammatory
Drugs (NSAIDs)
 Hemodynamycally- Induced ARF (Cont’d)

 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.
Nonsteroidal Anti-Inflammatory
Drugs (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 ?
Nonsteroidal Anti-Inflammatory
Drugs (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
Nonsteroidal Anti-Inflammatory
Drugs (NSAIDs)
 Analgesic nephropathy (Papillary necrosis and
chronic renal failure) cont’d
 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
 Nonsteroidal Anti-Inflammatory
Drugs (NSAIDs)
 Analgesic nephropathy (Papillary necrosis and
chronic renal failure) cont’d
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.
 Nonsteroidal Anti-Inflammatory
Drugs (NSAIDs)
• Analgesic nephropathy
 Excessive consumption of analgesics 100%
 Women 80%
 Headache 80%
 GIT disturbance 35%
 Urinary Tract. Infections 40%
 Papillary necrosis (clinical) 20%
 Papillary calcification 65%
 Nonsteroidal Anti-Inflammatory
Drugs (NSAIDs)
 Papillary necrosis
 Nonsteroidal Anti-Inflammatory
Drugs (NSAIDs)
 Papillary necrosis
 Nonsteroidal Anti-Inflammatory
Drugs (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
 ACE Inhibitors-Induced
Acute Renal Failure

 First group of antihypertensive drugs

shown to be renoprotective

 “High renin” patients are at risk:

 Bilateral (>70%) renal artery stenosis
 Moderate to Severe congestive hart failure
 Volume deleted (excessive use of diuretics)
 ACE Inhibitors-Induced
Acute Renal Failure
Control of Renin Secretion
 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 1
receptors → ↑ renin secretion
 ACE Inhibitors-Induced
Acute Renal Failure
INTRAGLOMERULAR PRESSURE

Arterial
pressure +
Angiotensin II Angiotensin II
+ + ++
Afferent 20 Efferent
arteriole mmHg
arteriole

Bowman’s
capsule
Renin Angiotensin System and
Efferent Arteriolar Constriction

Renal ischemia

Renin release

Angiotensin II formation

Efferent arteriolar constriction

Increased intraglomerular pressure

Maintained renal function

 ACE Inhibitors and
Efferent Arteriolar Constriction

Renal ischemia

Warnings for Renin release

use of ACEIs !!!

↓ Angiotensin II formation

Efferent arteriolar dilation

Reduced intraglomerular pressure

Reduced GFR
 CONGESTIVE HEART FAILURE

Angiotensinogen
diuretics
adrenergic AngI
stimulation
X ACEIs
Low poor renal perfusion
blood AngII
pressure sodium depletition
+ +++
Afferent Efferent
arteriole arteriole

Maintenance of
GFR at low rate
ACEIs may
cause renal
failure
 Calcineurin Inhibitors

Cyclosporin A [SANDIMMUNE®,
NEORAL®] Tracolimus [PRO-GRAF®]

 Mechanism or action

 Cyclosporin vs Tracolimus
 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)
 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

 Cyclosporine–induced hypertension
 Calcineurin Inhibitors
Chronic nephrotoxicity

 obliterative arteriolopathy
 vacuolization of the tubules
 focal areas of tubular atrophy
 interstitial fibrosis
 Crystal-Induced ARF

 Acyclovir (antiviral agent )

 Indinavir (antiretroviral agent, protease inhibitor)
 Methotrexate (antineoplastic agent,
antimetabolite)
 Sulfonamide antibiotics
 Triamterene
 Crystal-Induced ARF

Sulfonamide crystals
Indinavir sulfate
urinary crystals
Gagnon et al. 1998, Ann Intern Med 128-321
 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
 Nephrotoxic Drugs
• Prevention: General Rules
 Waspada terhadap obat yg bersifat nefrotoksik

 Identifikasi pasien resiko tinggi

 Waspada pemberian obat pada elderly

 tentukan benefit/risk ratio pda pemakaian obat

yg potentially nephrotoxic
 Nephrotoxic Drugs
• Prevention: General Rules (Cont’d)

 Hindari dehidrasi

 Limit dose and duration of treatment

 Adjust the dose based on changes in GFR

 Avoid a combination of potentially nephrotoxic

drugs