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FACULDADE DE MEDICINA DE SÃO JOSÉ DO RIO PRETO
Nefrotoxicidade Medicamentosa
Disciplina de Nefrologia
Emmanuel A. Burdmann
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• decreased GFR
• decreased renal reserve
• decreased RBF
• vasculature changes
• tubular changes
• drug excretion changes

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370,000 inhabitant Brazilian city
1717 selected individuals 1306 with Clcr
23.4 with Clcr
306
Burdmann, Cipullo et al WCN 2007
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Low ClCr - Age
37.7
Low ClCr ()
2.5
295
11

50y
Burdmann, Cipullo et al WCN 2007
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Low ClCr Age and Blood Pressure

• 50y 874 subjects
• 367 normal BP
• 507 hypertension 58

p 0.04
Low Clcr ()
37.7
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Normal BP
Hypertension
Burdmann, Cipullo et al WCN 2007
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NEFROTOXICIDADE MEDICAMENTOSA

• Prevalência e evolução
• Drogas mais comuns
• Aminoglicosídeos
• Contraste
• AINHs
• Bloqueadores EC
• Conclusão

• Mecanismos
• Frequência
• Fatores de risco
• Quadro clínico
• Prevenção

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58.818.3 y
58.920.1 y
58 (11)
265 (51)
201 (38)
NEPHROTOXICITY
ISCHEMIA
259/524 ATN drugs (with ischemia or alone)
Santos et al Crit Care 10R68, 2006
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?
AKI
CKD
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Contrast Induced AKI Effect on Mortality

• 16,248 pts
• 183 AKI
• 174 paired subjects

p
Death OR 5.5(2.91-13.19)
Mortality ()
Levy EM et al, JAMA 1996
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Aminoglycoside nephrotoxicity in the ICU -
Mortality
Mortality ()
93/209
44/151
Oliveira, Silva, Barbieri, Oliveira, Lobo, Lima,
Zanetta, Burdmann, ASN 2005
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Drug Nephrotoxicity

107/393 patients
Burdmann et al in Insuficiência Renal Aguda,
Schor, Boim and dos Santos, 1997
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DRUG NEPHROPATHY - PUBMED
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DRUGS NEPHROTOXICITY

• AMINOGLYCOSIDES

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AMINOGLYCOSIDE NEPHROTOXICITY
10 - 20 of therapeutic courses

• ENZYMURIA - (NAG, AAP, ?-GT)
• TUBULAR PROTEINURIA
• FANCONIS SYNDROME
• CA AND MG TUBULAR DEFECTS
• IMPAIRED ACID EXCRETION AND
• AMMONIA GENERATION
• TUBULAR RESISTANCE TO ADH
• ATN 7-10 DAYS, NON-OLIGURIC

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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

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Prevalence and risk factors for AG
nephrotoxicity in the ICU

• 360 consecutive ICU pts
• AKI GFR decrease from baseline20
• AKI 209 pts 58
• Mortality 44.5 vs. 29.1 (p0.0031)

Oliveira, Silva, Barbieri, Oliveira, Lobo, Lima,
Zanetta, Burdmann, ASN 2005
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Prevalence and risk factors for AG
nephrotoxicity in the ICU
Oliveira, Silva, Barbieri, Oliveira, Lobo, Lima,
Zanetta, Burdmann, ASN 2005
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Bactericidal activity
Single DD
Post-antibiotic effect
Multiple DD
Serum concentration
toxicity
t o x i c i t y
Time
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Aminoglycoside NephrotoxicityCircadian Variations

• 221 pts
• Gentamicin
• or
• Tobramycin
• Midnight to 730 AM

O.D.
Increase in Nephrotoxicity
Prins et al, Clin Pharmacol Ther, 1997
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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

Mortality ()
Nephrotoxicity ()
Bartal C et al, Am J Med 2003
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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
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Radiocontrast
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Contrast Nephrotoxicity Risk Factors
Cr 1.5 mg/dl
Erley CM and Porter GA. In Clinical
Nephrotoxins, De Broe et al, 2003
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Effect of Furosemide on Contrast Nephrotoxicity
Weinstein et col, Nephron 1992
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Prevention of Contrast Nephrotoxicity in Patients
With CRF
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Solomon et col, N Engl J Med, 1994
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Contrast Nephrotoxicity - Hydration Regimen
0.9 Saline (n 809) 0.45 Sodium Chloride (n
811)
0.45
0.45
0.45
0.9
0.9
0.9
Mueller et al, Arch Intern Med 2002
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Prevention of Contrast-Induced Nephropathy With
Sodium Bicarbonate A Randomized Controlled Trial

• 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.

2
17
Merten et al, JAMA 2004
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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
()
Rudnick et col, Kidney Int 1995
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Contrast nephrotoxicity Iso (iodixanol) vs.
low-osmolar (iohexol)
Iohexol
Iodixanol
0.5 mg/dl
1.0 mg/dl
Peak Increase in Serum Creatinine Concentration
Aspelin et al, N Engl J Med 2003
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Radiocontrast Nephrotoxicity Acetylcysteine
SCr change after 48 hrs
Incidence of Nephrotoxicity
()
D SCr (mg/dl)
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1.0
0.01
20
0.5
10
0.0
0
Placebo
Acty
-0.5
Placebo
Acty
Tepel et al, N Engl J Med 343 180, 2000
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Systematic review of the impact of
N-acetylcysteine on contrast nephropathy
P
Pannu N et al, Kidney Int 2004
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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.
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.
Pannu et al, Kidney Int 2004
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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 significant increase in the eGFR (P after the last dose of NAC.

Hoffmann et al, JASN 2004
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CONTRAST NEPHROTOXICITY - HEMOFILTRATION
Marenzi G et al, N Engl J Med, 2003
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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
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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
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Thomsen HS, Nephrol Dial Transplant 20 Suppl 1
i18, 2005
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NSAIDs
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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, 19992002.
• 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
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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
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NSAIDs Nephrotoxicity
Whelton et al In Clinical Nephrotoxins, De Broe
et al, 2003
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NSAID-induced AKI in hepatic cirrhosis
Zipser et al, J Clin Endocrinol Metab 1979
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Concomitant Use of Two or More NSAIDs - Side
Effects
Clinard F et al, Eur J Clin Pharmacol 2004
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NSAIDs NEPHROTOXICITY - TACROLIMUS
1.5
1.5
1.0
1.0

GFFR (ml/min/100 g)

0.5
0.5
SD
RO
VH
FK
FKSD
FKRO
RO
VH
FK
FKRO
SD sodium diclofenac RO rofecoxib FK
tacrolimus
Soubhia, Mendes, Mendonça, Cipullo, Burdmann,
Am J Nephrol 2005
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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
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ACE Inhibitor Nephrotoxicity
De Jong in Clinical Nephrotoxins, De Broe et al,
2003
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ACE Inhibitors Induced AKI

• Acute medical unit
• 2,398 consecutive admissions
• 89 pts (3.7) with SCradm ³ 200 µmol/L
• 9 on regular dialysis
• 30/80 (37.5) on ACE inhibitors
• 6/30 (20) diarrhea and/or vomiting

SCr (µmol/L)
Stirling C et al, J Hum Hypertens 2003
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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 discontinue or change dosage
Salomon L et al, Int J Qual Health Care 2003
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DRUGS NEPHROTOXICITY

• Costly
• Deadly
• Predictable
• Preventable !!!

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• Avoid drug, when possible
• Baseline renal function
• Monitoring renal function
• Hydration
• Specific maneuvers

PREVENTION OF DRUGS NEPHROTOXICITY
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• 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

• William Bennett
• Takeshi Andoh
• Jessie Lindsley
• Richard Johson
• Luis Yu
• Isac de Castro
• Benedito J. Pereira
• Terezila Coimbra
• Suzana Lobo
• Emerson Q. Lima