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FACULDADE DE MEDICINA DE SÃO JOSÉ DO RIO PRETO

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.

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FACULDADE DE MEDICINA DE SÃO JOSÉ DO RIO PRETO

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  1. FACULDADE DE MEDICINA DE SÃO JOSÉ DO RIO PRETO Nefrotoxicidade Medicamentosa Disciplina de Nefrologia Emmanuel A. Burdmann

  2. decreased GFR • decreased renal reserve • decreased RBF • vasculature changes • tubular changes • drug excretion changes

  3. 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

  4. Low ClCr - Age 37.7% Low ClCr (%) 2.5% 295 11 < 50y ≥ 50y Burdmann, Cipullo et al WCN 2007

  5. Low ClCr – Age and Blood Pressure • ≥ 50y: 874 subjects: • 367 normal BP • 507 hypertension: 58 % p = 0.04 Low Clcr (%) 37.7% 28% Normal BP Hypertension Burdmann, Cipullo et al WCN 2007

  6. NEFROTOXICIDADE MEDICAMENTOSA • Prevalência e evolução • Drogas mais comuns • Aminoglicosídeos • Contraste • AINHs • Bloqueadores EC • Conclusão • Mecanismos • Frequência • Fatores de risco • Quadro clínico • Prevenção

  7. 58.8±18.3 y 58.9±20.1 y 58 (11%) 265 (51%) 201 (38%) NEPHROTOXICITY ISCHEMIA 259/524 ATN: drugs (with ischemia or alone) Santos et al: Crit Care 10:R68, 2006

  8. + ? CKD AKI

  9. Contrast Induced AKI – Effect on Mortality • 16,248 pts • 183 AKI • 174 paired subjects p < 0.001 Death OR 5.5(2.91-13.19) Mortality (%) Levy EM et al, JAMA 1996

  10. Aminoglycoside nephrotoxicity in the ICU - Mortality Mortality (%) 93/209 44/151 Oliveira, Silva, Barbieri, Oliveira, Lobo, Lima, Zanetta, Burdmann, ASN 2005

  11. DrugNephrotoxicity % 107/393 patients Burdmann et al in: Insuficiência Renal Aguda, Schor, Boim and dos Santos, 1997

  12. DRUG NEPHROPATHY - PUBMED

  13. DRUGS NEPHROTOXICITY AMINOGLYCOSIDES

  14. 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

  15. 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

  16. Prevalence and risk factors for AG nephrotoxicity in the ICU • 360consecutive 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

  17. Prevalence and risk factors for AG nephrotoxicity in the ICU Oliveira, Silva, Barbieri, Oliveira, Lobo, Lima, Zanetta, Burdmann, ASN 2005

  18. Bactericidal activity Single DD Post-antibiotic effect Multiple DD Serum concentration toxicity t o x i c i t y Time

  19. Aminoglycoside NephrotoxicityCircadian Variations • 221 pts • Gentamicin or Tobramycin • Midnight to 7:30 AM • O.D. • Increase in Nephrotoxicity Prins et al, Clin Pharmacol Ther, 1997

  20. 0.03 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

  21. Economic Impact of Aminoglycoside ToxicityDrug Monitoring 15% • 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

  22. Radiocontrast

  23. Contrast Nephrotoxicity Risk Factors Cr > 1.5 mg/dl Erley CM and Porter GA. In: Clinical Nephrotoxins, De Broe et al, 2003

  24. Effect of Furosemide on Contrast Nephrotoxicity Weinstein et col, Nephron 1992

  25. Prevention of Contrast Nephrotoxicity in Patients With CRF 11% 40 % 28 % Solomon et col, N Engl J Med, 1994

  26. 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

  27. 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

  28. 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

  29. 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

  30. Radiocontrast Nephrotoxicity Acetylcysteine SCr change after 48 hrs Incidence of Nephrotoxicity (%) D SCr (mg/dl) 30 < 0.001 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

  31. Systematic review of the impact of N-acetylcysteine on contrast nephropathy P< 0.02 Pannu N et al, Kidney Int 2004

  32. 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

  33. 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

  34. CONTRAST NEPHROTOXICITY - HEMOFILTRATION Marenzi G et al, N Engl J Med, 2003

  35. 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

  36. 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]

  37. Thomsen HS, Nephrol Dial Transplant 20 Suppl 1: i18, 2005

  38. NSAIDs

  39. 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

  40. 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

  41. NSAIDs Nephrotoxicity Whelton et al In: Clinical Nephrotoxins, De Broe et al, 2003

  42. NSAID-induced AKI in hepatic cirrhosis Zipser et al, J Clin Endocrinol Metab 1979

  43. Concomitant Use of Two or More NSAIDs - Side Effects Clinard F et al, Eur J Clin Pharmacol 2004

  44. * p < 0.001 vs. SD, VH, FK ** p < 0.05 vs. RO, VH 0.01 NSAIDs NEPHROTOXICITY - TACROLIMUS 1.5 1.5 1.0 1.0 ** GFFR (ml/min/100 g) * 0.5 0.5 SD RO RO VH VH FK FK FK+SD FK+RO FK+RO SD: sodium diclofenac RO: rofecoxib FK: tacrolimus Soubhia, Mendes, Mendonça, Cipullo, Burdmann, Am J Nephrol 2005

  45. 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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