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FACULDADE DE MEDICINA DE
SÃO JOSÉ DO RIO PRETO
Nefrotoxicidade
Medicamentosa
Disciplina de Nefrologia
Emmanuel A. Burdmann
 decreased GFR
 decreased renal reserve
 decreased RBF
 vasculature changes
 tubular changes
 drug excretion changes
370,000 inhabitant Brazilian city
1717 selected individuals
1306 with Clcr
23.4% with Clcr < 60 mL/min/1.73m2
306
Burdmann, Cipullo et al WCN 2007
Low ClCr - Age
37.7%
Low ClCr (%)
2.5%
11
< 50y
295
≥ 50y
Burdmann, Cipullo et al WCN 2007
Low ClCr – Age and Blood Pressure
 ≥ 50y: 874 subjects:
 367 normal BP
 507 hypertension: 58 %
p = 0.04
Low Clcr (%)
50
40
30
20
28%
37.7%
10
0
Normal BP
Burdmann, Cipullo et al WCN 2007
Hypertension
NEFROTOXICIDADE
MEDICAMENTOSA
 Prevalência e evolução
 Drogas mais comuns
 Aminoglicosídeos
 Contraste
 AINHs
 Bloqueadores EC
Conclusão
 Mecanismos
 Frequência
 Fatores de risco
 Quadro clínico
 Prevenção
58.8±18.3 y
ISCHEMIA
265
(51%)
201
(38%)
58.9±20.1 y
58
(11%)
NEPHROTOXICITY
259/524 ATN: drugs
(with ischemia or alone)
Santos et al: Crit Care 10:R68, 2006
+
?
AKI
CKD
Contrast Induced AKI – Effect on Mortality
p < 0.001
•
16,248 pts
•
183 AKI
•
174 paired subjects
35
Mortality (%)
30
Death OR 5.5
(2.91-13.19)
25
20
15
10
5
0
No ARF
Levy EM et al, JAMA 1996
ARF
Aminoglycoside nephrotoxicity in the ICU - Mortality
p=0.0031
Mortality
Mortality (%)
(%)
45
30
44/151
93/209
Stable GFR
GFR decrease
15
0
Oliveira, Silva, Barbieri, Oliveira, Lobo, Lima, Zanetta, Burdmann, ASN 2005
Drug Nephrotoxicity
%
107/393 patients
70
60
50
40
30
20
10
0
Antibiotics Contrast
NSAIDs
ACE
CsA
Burdmann et al in: Insuficiência Renal Aguda, Schor, Boim and dos Santos, 1997
DRUG NEPHROPATHY - PUBMED
12,000
10,000
hits
8,000
6,000
4,000
2,000
0
Contrast
NSAIDs
AG
CNI
Cisplatin
Other
anti-infectious
DRUGS
NEPHROTOXICITY
AMINOGLYCOSIDES
AMINOGLYCOSIDE NEPHROTOXICITY
10 - 20% of therapeutic courses
• ENZYMURIA - (NAG, AAP, -GT)
• TUBULAR PROTEINURIA
• FANCONI’S SYNDROME
• CA++ AND MG++ TUBULAR DEFECTS
• IMPAIRED ACID EXCRETION AND
•
AMMONIA GENERATION
TUBULAR RESISTANCE TO ADH
•ATN: 7-10 DAYS, NON-OLIGURIC
AMINOGLYCOSIDE NEPHROTOXICITY
RISK FACTORS ?
• ADVANCED AGE
• PROLONGED EXPOSURE
• VOLUME CONTRACTION
• PREEXISTING RENAL INSUFFICIENCY
• CONCOMITANT NEPHROTOXIN EXPOSURE
•
•
•
(CsA, contrast, AmB, cephalosporins, vanco)
POTASSIUM DEPLETION
ACIDOSIS
CONCURRENT HEPATOTOXICITY
Prevalence and risk factors for AG
nephrotoxicity in the ICU
360 consecutive ICU pts
AKI: GFR decrease from baseline>20%
AKI 209 pts: 58%
Mortality 44.5% vs. 29.1% (p=0.0031)
Oliveira, Silva, Barbieri, Oliveira, Lobo, Lima, Zanetta, Burdmann, ASN 2005
Prevalence and risk factors for AG
nephrotoxicity in the ICU
OR (CI 95%)
p
Baseline GFR < 60
ml/min/1.73 m2
0.42 (0.24 – 0.72)
0.02
Diabetes
2.13 (1.01 – 4.49)
0.046
Contrast
2.13 (1.02 – 4.43)
0.043
Hypotension
1.83 (1.14 – 2.94)
0.012
Other NTx ATB
1.61 (1.00 – 2.59)
0.048
Oliveira, Silva, Barbieri, Oliveira, Lobo, Lima, Zanetta, Burdmann, ASN 2005
Serum concentration
Single DD
Bactericidal activity
Post-antibiotic effect
Multiple DD
toxicity
toxicity
Time
Aminoglycoside Nephrotoxicity
Circadian Variations
• 221 pts
• Gentamicin
or
O.D.
Tobramycin
• Midnight to 7:30 AM
Increase in
Nephrotoxicity
Prins et al, Clin Pharmacol Ther, 1997
Aminoglycoside Nephrotoxicity
Pharmacokinetic Dosing
Pharmacokinetic group: 43 pts
Fixed OD dosage: 38 pts
Gentamicin or Amikacin
Renal toxicity: ≥ 25% in SCr or SCr > 1.4 mg/dL
0.03
30
Mortality (%)
Nephrotoxicity (%)
25
20
15
10
25
20
15
10
5
5
0
0
PG
ODG
PG
ODG
Bartal C et al, Am J Med 2003
Economic Impact of Aminoglycoside Toxicity
Drug Monitoring
• Nephrotoxicity:
– US$ 4,583.00/patient
• Therapeutic drug monitoring:
– US$ 301.87/patient
• TDM of 100 patients:
15%
– US$ 30,187.00
25
20
• If nephrotoxicity  6.6%:
– US$ 30,284.00 saving
15
10
5
0
PG
ODG
Slaughter and Cappelletty, Pharmacoeconomics, 1998
Radiocontrast
Contrast Nephrotoxicity
Risk Factors
Cr > 1.5 mg/dl
Erley CM and Porter GA. In: Clinical Nephrotoxins, De Broe et al, 2003
Effect of Furosemide on Contrast
Nephrotoxicity
Weinstein et col, Nephron 1992
Prevention of Contrast Nephrotoxicity in Patients With CRF
11%
Solomon et col, N Engl J Med, 1994
28 %
40 %
Contrast Nephrotoxicity - Hydration Regimen
0.9% Saline (n= 809)
0.45% Sodium Chloride (n= 811)
0.9%
0.45%
0.45%
0.45%
0.9%
0.9%
Mueller et al, Arch Intern Med 2002
Prevention of Contrast-Induced Nephropathy With Sodium Bicarbonate
A Randomized Controlled Trial
Prospective, randomized
iopamidol administration
(370 mg iodine/mL).
2%
17%
119 patients
59 sodium chloride
60 sodium bicarbonate
154-mEq/L infusion
3 mL/kg per hour for 1
hour before contrast,
followed by 1 mL/kg per hour
for 6 hours during and after
the procedure.
Merten et al, JAMA 2004
Nephrotoxicity of Nonionic and Ionic Contrast Media in
1196 Patients: a Randomized Trial
Nephrotoxicity: Cr increase ≥ 1.0 mg/dL 48-72 hours after contrast
30
25
(%)
20
15
10
5
0
Total
P<0.002
Rudnick et col, Kidney Int 1995
Group 1
(-)RI(-)DM
Group 2
(-)RI(+)DM
Group 3
(+)RI(-)DM
Group 4
(+)RI(+)DM
Contrast nephrotoxicity
Iso (iodixanol) vs. low-osmolar (iohexol)
Iohexol
No. of Patients
Iodixanol
≥ 0.5 mg/dl
≥ 1.0 mg/dl
Peak Increase in Serum Creatinine Concentration
Aspelin et al, N Engl J Med 2003
Radiocontrast Nephrotoxicity
Acetylcysteine
SCr change after 48 hrs
(%)
D SCr (mg/dl)
1.0
Incidence of Nephrotoxicity
30
< 0.001
0.01
20
0.5
10
0.0
0
-0.5
Placebo
Placebo
Acty
Acty
Tepel et al, N Engl J Med 343: 180, 2000
Systematic review of the impact of
N-acetylcysteine on contrast nephropathy
P< 0.02
Pannu N et al, Kidney Int 2004
Systematic review of the impact of
N-acetylcysteine on contrast nephropathy
NAC
may
reduce
the incidence
of of
Before
NAC
becomes
the standard
acutely
serum
creatinine
care forincreased
all patients
receiving
after
administration
ofnew
intravenous
intravenous
contrast,
contrast,
buttrials
this finding
was its
of
randomized
evaluating
borderline
statistical
significance,
effect on clinically
relevant
and
there was
significant
outcomes
are required.
heterogeneity between trials.
Pannu et al, Kidney Int 2004
The value of N-acetylcysteine in the prevention of radiocontrast agent-induced
nephropathy seems questionable.
 50 healthy volunteers
NAC was administered
orally at a dose of 600 mg
every 12 h, for a total of
four doses
There was a significant
decrease in the mean
serum creatinine
concentration (P < 0.05)
and a significant increase
in the eGFR (P < 0.02) 4 h
after the last dose of NAC.
Hoffmann et al, JASN 2004
CONTRAST NEPHROTOXICITY - HEMOFILTRATION
CONTROL
HF
(N=56)
(N=58)
P
SCr increase (>25%)
50%
5%
<0.001
Temporary RRT
25%
3%
In hospital events
52%
9%
<0.001
In hospital mortality
14%
2%
0.02
1 year mortality
30%
10%
0.01
Marenzi G et al, N Engl J Med, 2003
Gadolinium-based contrast agents and nephrotoxicity in
patients undergoing coronary artery procedures.
 Pts with SCr ≥2.0 mg/dl and/or CrCl ≤ 40 ml/min.
 25 pts received gadolinium-based contrast vs 32 pts with iodinated isoosmolality contrast agent selected from database (control group).
 Prophylactic 0.45% saline intravenously and NAC (1.2 g PO twice daily).
 Similar baseline creatinine and creatinine clearance (Gadolinium 2.30
mg/dl and 33 ml/min vs. Iodinated 2.24 mg/dl and 30 ml/min).
 Increase Scr ≥ 0.5 mg/dl (48 hr) in 28% of the Gadolinium
group vs. 6.5% in the iodinated group (p = 0.034).
 Renal failure requiring temporary dialysis in 8% of the
Gadolinium group and in 0% in the iodinated group (p = 0.19).
Briguori C et al, Catheter Cardiovasc Interv 2006
Gadolinium contrast media are more
nephrotoxic than iodine media. The importance
of osmolality in direct renal artery injections
Barbara Elmståhl , Ulf Nyman, Peter Leander, Chun-Ming Chai,
Klaes Golman, Jonas Björk and Torsten Almén
 Gadodiamide (0.78 Osm/kg H(2)O) Vs iohexol (0.42
Osm/kg H(2)O).
 Renal artery of eight left-sided nephrectomized pigs.
 Plasma half-life of a GFR marker was used to compare
effects 1-3 h post-injection.
“Iohexol molecules were less nephrotoxic
than the Gd-CM molecules.”
Eur Radiol. 2006 Aug 5; [Epub ahead of print]
Thomsen HS, Nephrol Dial Transplant 20 Suppl 1: i18, 2005
NSAIDs
Association of Selective and Conventional
Nonsteroidal Antiinflammatory Drugs with
Acute Renal Failure: A Population-based,
Nested Case-Control Analysis
Administrative health care databases, Quebec, Canada,
1999–2002.
121,722 new NSAID users > 65 y
4,228 cases of AKI
- 1.48 cases/100 person-years
- Case fatality 47.3%
84,540 controls (matched age, follow-up time)
Conditional logistic regression, adjusted for sex, age,
health status, health care utilization measures, exposure to
contrast agents, and nephrotoxic medications.
Schneider et al, Am J Epidemiol, Epub Sep 2006
Association of Selective and Conventional
Nonsteroidal Antiinflammatory Drugs with
Acute Renal Failure: A Population-based,
Nested Case-Control Analysis
NSAIDs
RR
CI (95%)
All
2.05
1.61 – 2.60
Rofecoxib
2.31
1.73 – 3.08
Naproxen
2.42
1.52 – 3.85
Non selective/non naproxen
2.30
1.60 – 3.32
Celecoxib
1.54
1.14 – 2.09
Schneider et al, Am J Epidemiol, Epub Sep 2006
NSAIDs Nephrotoxicity
Whelton et al In: Clinical Nephrotoxins, De Broe et al, 2003
NSAID-induced AKI in hepatic cirrhosis
Zipser et al, J Clin Endocrinol Metab 1979
Concomitant Use of Two
or More NSAIDs - Side Effects
One
Two or More
OR
95% CI
OR
95% CI
AKI
3.2
2.5-4.1
4.8
2.6-8.8
Hepatic Injury
1.2
0.9-1.5
2.2
1.3-3.8
GI bleeding
7.3
4.9-10.9
10.7
2.9-40.2
Clinard F et al, Eur J Clin Pharmacol 2004
NSAIDs NEPHROTOXICITY - TACROLIMUS
* p < 0.001 vs. SD, VH, FK
GFFR (ml/min/100 g)
1.5
** p < 0.05 vs. RO, VH
0.01
1.0
**
*
0.5
SD
RO
VH
FK
FK+SD FK+RO
SD: sodium diclofenac
RO: rofecoxib
FK: tacrolimus
Soubhia, Mendes, Mendonça, Cipullo, Burdmann, Am J Nephrol 2005
CKD & long-term use of NSAIDs
• prospective study
• 259 heavy analgesic users, 11-year-period
• 69 new cases of analgesic nephropathy with
renal papillary necrosis
• 42% excessive quantities of NSAIDs alone
• 13% NSAIDs in combinations with
paracetamol, aspirin, phenacetin, caffeine,
and/or traditional herbal medications.
• amount of NSAIDs ranged from 1,000 to
26,600 capsules or tablets over a 2- to 25year period.
• SCr 126 to 778 mumol/L in 64.8%.
Segasothy et al, Am J Kidney Dis 1994
ACE Inhibitor Nephrotoxicity
De Jong in Clinical Nephrotoxins, De Broe et al, 2003
ACE Inhibitors – Induced AKI
Acute medical unit
2,398 consecutive admissions
89 pts (3.7%) with SCradm  200 µmol/L
9 on regular dialysis
30/80 (37.5%) on ACE inhibitors
6/30 (20%) – diarrhea and/or vomiting
300
250
SCr (µmol/L)




200
150
100
50
0
Baseline
Stirling C et al, J Hum Hypertens 2003
Hospital Admission
ACE Withdrawal
Fluid Replacement
Renal Impairment vs Prescribing Behavior
•
•
•
•
French teaching hospital
71/118 residents  questionnaire
Drug prescription in 4 patients with renal impairment
Order:
– Gentamicin Maintain or
– Diclofenac
discontinue or
– Amlodipine
change dosage
– 4th drug to start (enalapril): 3 doses or not prescribing
• Inappropriate order (renal function):
Gentamicin: 62%
Diclofenac: 42%
Enalapril: 52%
• Inadequate decrease of amlodipine: 28%
Salomon L et al, Int J Qual Health Care 2003
DRUGS NEPHROTOXICITY
 Costly
 Deadly
 Predictable
 Preventable !!!
Avoid
drug, when possible
PREVENTION
Baseline renal function
OF
DRUGS
Monitoring renal function
NEPHROTOXICITY
Hydration
Specific maneuvers
•
•
•
•
•
•
•
•
•
•
William Bennett
Takeshi Andoh
Jessie Lindsley
Richard Johson
Luis Yu
Isac de Castro
Benedito J. Pereira
Terezila Coimbra
Suzana Lobo
Emerson Q. Lima
•
•
•
•
•
•
•
•
•
•
•
Glória Elisa
Dirce M. T. Zanetta
José P. Cipullo
Maria A. Baptista
Rosa Soubhia
Vera Ramalho
Ivan M. Araujo
José M. Vieira Jr
João F. P. Oliveira
Adriana I. Joaquim
Wilson J. Q. Santos