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