Post on 16-Jan-2016
FACULDADE DE MEDICINA DE FACULDADE DE MEDICINA DE SÃO JOSÉ DO RIO PRETOSÃO JOSÉ DO RIO PRETO
Nefrotoxicidade Nefrotoxicidade MedicamentosaMedicamentosa
Emmanuel A. BurdmannEmmanuel A. Burdmann
Disciplina de NefrologiaDisciplina de Nefrologia
decreased GFR
decreased renal reserve
decreased RBF
vasculature changes
tubular changes
drug excretion changes
1717 selected individuals 1306 with Clcr
306
23.4% with Clcr < 60 mL/min/1.73m2
370,000 inhabitant Brazilian city
Burdmann, Cipullo et al WCN 2007
Low ClCr - AgeLow ClCr - Age
11
< 50y ≥ 50y
2952.5%
37.7%Low ClCr (%)
Burdmann, Cipullo et al WCN 2007
Low ClCr – Age and Blood PressureLow ClCr – Age and Blood Pressure
0
10
20
30
40
50
Normal BP Hypertension
28% 37.7%
Low Clcr (%)p = 0.04
≥ 50y: 874 subjects:
367 normal BP
507 hypertension: 58 %
Burdmann, Cipullo et al WCN 2007
NEFROTOXICIDADE NEFROTOXICIDADE MEDICAMENTOSAMEDICAMENTOSA
Prevalência e evolução
Drogas mais comuns
Aminoglicosídeos
Contraste
AINHs
Bloqueadores EC
Conclusão
Mecanismos
Frequência
Fatores de risco
Quadro clínico
Prevenção
ISCHEMIAISCHEMIA NEPHROTOXICITYNEPHROTOXICITY265(51%)
201(38%)
58(11%)
Santos et al: Crit Care 10:R68, 2006Santos et al: Crit Care 10:R68, 2006
259/524 ATN: drugs (with ischemia or
alone)
58.8±18.3 y 58.9±20.1 y
+
?
AKI CKD
Contrast Induced AKI – Effect on Mortality
0
5
10
15
20
25
30
35
No ARF ARF
Mo
rta
lity
(%
)
Levy EM et al, JAMA 1996Levy EM et al, JAMA 1996
• 16,248 pts
• 183 AKI
• 174 paired subjectsp < 0.001
Death OR 5.5
(2.91-13.19)
Aminoglycoside nephrotoxicity in the ICU - Mortality
Stable GFR GFR decrease
0
15
30
45
p=0.0031M
ortali
ty (%
)
Oliveira, Silva, Barbieri, Oliveira, Lobo, Lima, Zanetta, Burdmann, ASN 2005
93/20944/151
Mort
ality
(%
)
DrugDrug NephrotoxicityNephrotoxicity
0
10
20
30
40
50
60
70
Antibiotics Contrast NSAIDs ACE CsA
Burdmann et al in: Insuficiência Renal Aguda, Schor, Boim and dos Santos, 1997Burdmann et al in: Insuficiência Renal Aguda, Schor, Boim and dos Santos, 1997
107/393 107/393 patientspatients%
DRUG NEPHROPATHY - PUBMED
0
2,000
4,000
6,000
8,000
10,000
12,000
NSAIDsContrast AG CNI Cisplatin Otheranti-infectious
hit
s
DRUGS NEPHROTOXICITY
AMINOGLYCOSIDES
AMINOGLYCOSIDE NEPHROTOXICITY
• 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-OLIGURICATN: 7-10 DAYS, NON-OLIGURIC
10 - 20% of therapeutic courses
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
Oliveira, Silva, Barbieri, Oliveira, Lobo, Lima, Zanetta, Burdmann, ASN 2005
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)
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
Time
Seru
m c
on
cen
trati
on
Single DD
Multiple DD
Bactericidal activity
Post-antibiotic effect
toxicity t o x i c i t y
• 221 pts221 pts
• GentamicinGentamicin
oror
TobramycinTobramycin
• Midnight to 7:30 AMMidnight to 7:30 AM
Aminoglycoside NephrotoxicityAminoglycoside NephrotoxicityCircadian VariationsCircadian Variations
O.D.O.D.
Increase in Increase in NephrotoxicitNephrotoxicit
yyPrins et al, Clin Pharmacol Ther, 1997Prins et al, Clin Pharmacol Ther, 1997
Aminoglycoside Nephrotoxicity Aminoglycoside Nephrotoxicity Pharmacokinetic DosingPharmacokinetic Dosing
Ne
ph
roto
xic
ity
(%
)
Bartal C et al, Am J Med 2003Bartal C et al, Am J Med 2003
Pharmacokinetic group: 43 ptsPharmacokinetic group: 43 pts
Fixed OD dosage: 38 ptsFixed OD dosage: 38 pts
Gentamicin or AmikacinGentamicin or Amikacin
Renal toxicity: Renal toxicity: ≥ 25% in SCr or SCr > 1.4 mg/dL ≥ 25% in SCr or SCr > 1.4 mg/dL
0
5
10
15
20
25
30
PG ODG0
5
10
15
20
25
PG ODG
0.03
Mo
rta
lity
(%
)
Economic Impact of Aminoglycoside ToxicityDrug Monitoring
• Nephrotoxicity:
– US$ 4,583.00/patient
• Therapeutic drug monitoring:
– US$ 301.87/patient
• TDM of 100 patients:
– US$ 30,187.00
• If nephrotoxicity 6.6%:
– US$ 30,284.00 saving
Slaughter and Cappelletty, Pharmacoeconomics, 1998
0
5
10
15
20
25
PG ODG
15%
Radiocontrast
Contrast Nephrotoxicity Contrast Nephrotoxicity Risk Factors Risk Factors
Erley CM and Porter GA. In: Clinical Nephrotoxins, De Broe et al, Erley CM and Porter GA. In: Clinical Nephrotoxins, De Broe et al, 20032003
Cr > 1.5 mg/dl
Weinstein et col, Nephron 1992Weinstein et col, Nephron 1992
Effect of Furosemide on Effect of Furosemide on Contrast NephrotoxicityContrast Nephrotoxicity
Prevention of Contrast Nephrotoxicity in Patients With Prevention of Contrast Nephrotoxicity in Patients With CRF CRF
Solomon et col, N Engl J Med, 1994Solomon et col, N Engl J Med, 1994
11% 28 % 40 %
Mueller et al, Arch Intern Med 2002
Contrast Nephrotoxicity - Hydration Contrast Nephrotoxicity - Hydration Regimen Regimen
0.9%
0.45%
0.9%
0.9%
0.45%
0.45%
0.9% Saline (n= 809) 0.45% Sodium Chloride (n= 811)
17%2%
Prevention of Contrast-Induced Nephropathy With Sodium BicarbonateA Randomized Controlled Trial
Merten et al, JAMA 2004
Prospective, randomized
iopamidol administration (370 mg iodine/mL).
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.
Nephrotoxicity of Nonionic and Ionic Contrast Nephrotoxicity of Nonionic and Ionic Contrast
Media in 1196 Patients: Media in 1196 Patients: a Randomized Triala Randomized Trial
Rudnick et col, Kidney Int 1995Rudnick et col, Kidney Int 1995
Nephrotoxicity: Cr increase ≥ 1.0 mg/dL 48-72 hours after contrastNephrotoxicity: Cr increase ≥ 1.0 mg/dL 48-72 hours after contrast
0
5
10
15
20
25
30
TotalP<0.002
Group 1 (-)RI(-)DM
Group 2 (-)RI(+)DM
Group 3(+)RI(-)DM
Group 4(+)RI(+)DM
(%
)
Aspelin et al, N Engl J Med 2003
Contrast nephrotoxicityIso (iodixanol) vs. low-osmolar (iohexol)
Peak Increase in Serum Creatinine Concentration
Iodixanol Iohexol
≥ 0.5 mg/dl ≥ 1.0 mg/dl
No. of
Pat
ients
Placebo Acty-0.5
0.0
0.5
1.0
Placebo Acty0
10
20
30
Tepel et al, N Engl J Med 343: 180, 2000Tepel et al, N Engl J Med 343: 180, 2000
Radiocontrast Nephrotoxicity Radiocontrast Nephrotoxicity AcetylcysteineAcetylcysteine
SCr change after 48 hrsSCr change after 48 hrs Incidence of NephrotoxicityIncidence of Nephrotoxicity
(%)(%) SCr (mg/dl)SCr (mg/dl)
< 0.001< 0.0010.010.01
Pannu N et al, Kidney Int 2004
P< 0.02
Systematic review of the impact of N-acetylcysteine on contrast nephropathy
NAC may reduce the incidence of acutely increased serum creatinine after administration of intravenous contrast, but this finding was of borderline statistical significance, and there was significant heterogeneity between trials.
Systematic review of the impact of N-acetylcysteine on contrast nephropathy
Pannu et al, Kidney Int 2004
Before NAC becomes the standard of care for all patients receiving intravenous contrast, new randomized trials evaluating its effect on clinically relevant outcomes are required.
The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable.
Hoffmann et al, JASN 2004
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.
CONTRAST NEPHROTOXICITY - HEMOFILTRATION
CONTROL(N=56)
HF(N=5
8)
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 iso-osmolality 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
Eur Radiol. 2006 Aug 5; [Epub ahead of print]
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.”
Thomsen HS, Nephrol Dial Transplant 20 Suppl 1: i18, 2005
NSAIDsNSAIDs
Association of Selective and Conventional Nonsteroidal Antiinflammatory Drugs with Acute Renal Failure: A Population-based, Nested Case-Control Analysis
Schneider et al, Am J Epidemiol, Epub Sep 2006
Administrative health care databases, Quebec, Canada, 1999–2002.121,722 new NSAID users > 65 y4,228 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.
Association of Selective and Conventional Nonsteroidal Antiinflammatory Drugs with Acute Renal Failure: A Population-based, Nested Case-Control Analysis
Schneider et al, Am J Epidemiol, Epub Sep 2006
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
NSAIDs NephrotoxicityNSAIDs Nephrotoxicity
Whelton et al In: Clinical Nephrotoxins, De Broe et al, 2003Whelton et al In: Clinical Nephrotoxins, De Broe et al, 2003
NSAID-induced AKI in hepatic cirrhosis
Zipser et al, J Clin Endocrinol Metab 1979
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
Concomitant Use of Two or More NSAIDs - Side Effects
Clinard F et al, Eur J Clin Pharmacol 2004Clinard F et al, Eur J Clin Pharmacol 2004
GF
FR
(m
l/min
/10
0 g
)
SD RO VH FK FK+SD FK+RO
0.5
1.0
1.5** p < 0.05 vs. RO, VH
* p < 0.001 vs. SD, VH, FK
*
**
RO VH FK FK+RO
0.5
1.0
1.5
SD: sodium diclofenac
RO: rofecoxibrofecoxib
FK: tacrolimus
0.01
Soubhia, Mendes, Mendonça, Cipullo, Burdmann, Am J Nephrol 2005
NSAIDs NEPHROTOXICITY - TACROLIMUS
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 25-year period.
•SCr 126 to 778 mumol/L in 64.8%.
Segasothy et al, Am J Kidney Dis 1994
ACE Inhibitor NephrotoxicityACE Inhibitor Nephrotoxicity
De Jong De Jong inin Clinical Nephrotoxins, De Broe et al, 2003 Clinical Nephrotoxins, De Broe et al, 2003
ACE Inhibitors – Induced AKI
Stirling C et al, J Hum Hypertens Stirling C et al, J Hum Hypertens 20032003
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
0
50
100
150
200
250
300
Baseline Hospital Admission ACE Withdrawal Fluid Replacement
SC
r (µ
mol/
L)
Renal Impairment vs Prescribing Behavior
• French teaching hospital
• 71/118 residents questionnaire
• Drug prescription in 4 patients with renal impairment
• Order:
– Gentamicin
– Diclofenac
– Amlodipine
– 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%
Maintain or Maintain or
discontinue discontinue or or
change change dosagedosage
Salomon L et al, Int J Qual Health Care 2003Salomon L et al, Int J Qual Health Care 2003
DRUGS NEPHROTOXICITY
Costly
Deadly
Predictable
Preventable !!!
PREVENTION
OF DRUGS
NEPHROTOXICITY
Avoid drug, when Avoid drug, when possiblepossible
Baseline renal functionBaseline renal function
Monitoring renal Monitoring renal functionfunction
HydrationHydration
Specific maneuversSpecific maneuvers
• William BennettWilliam Bennett• Takeshi AndohTakeshi Andoh• Jessie LindsleyJessie Lindsley• Richard JohsonRichard Johson• Luis YuLuis Yu• Isac de CastroIsac de Castro• Benedito J. PereiraBenedito J. Pereira• Terezila CoimbraTerezila Coimbra• Suzana LoboSuzana Lobo• Emerson Q. LimaEmerson Q. Lima
• Glória ElisaGlória Elisa• Dirce M. T. ZanettaDirce M. T. Zanetta• José P. CipulloJosé P. Cipullo• Maria A. BaptistaMaria A. Baptista• Rosa SoubhiaRosa Soubhia• Vera RamalhoVera Ramalho• Ivan M. AraujoIvan M. Araujo• José M. Vieira JrJosé M. Vieira Jr• João F. P. OliveiraJoão F. P. Oliveira• Adriana I. JoaquimAdriana I. Joaquim• Wilson J. Q. SantosWilson J. Q. Santos