Vancomycin nephrotoxicity: frequency and mechanistic aspects

Transcription

1 Vancomycin nephrotoxicity: frequency and mechanistic aspects April 24th 2018 Yosu LUQUE Urgences Néphrologiques et Transplantation rénale Hôpital Tenon, Paris

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4 Late 40 s: Penicillin-resistant staphylococcus aureus

5 Edmund Carl Kornfeld, Eli Lilly and Company, USA Borneo, 1953 Streptomyces orientalis Vancomycin isolated: «Vanquish» Staphylococcus

6 1953: Vancomycin discovery 1959: Methicillin FDA approval 70 s: Methicillin resistant Staphylococcus aureus 1958: Vancomycin FDA approval Rybak MJ et al. J Antimicrob Chemother Levine et al. Cin Inf Diseases 2006

7 MRSA NSPP Clostridium difficile VRE Clin Infect Dis Vancomycin: a history. Levine DP.

8 Wood et al Aronoff et al : The Mississippi mud Ototoxicity / Nephrotoxicity +++ After 1970: purified Vancomycin Rybak MJ et al. J Antimicrob Chemother Limited indications AKI: 5-10% Can reach 35% if associated to aminoglycosides Farber et al Mellor et al s experimental models: Vancomycin monotherapy nephrotoxicity (controversial data ) Synergic toxicity with aminoglycosides (tobramycin)

9 Decreased GFR Trough levels >15-20 mg/l Renal excretion Small peptide (1,5 kda) Timing? Therapy lenght > days Other nephrotoxic drugs? Obesity Dosage / Theraphy length Ideal body weight versus body weight >4g/day Continuous vs. Intermittent? Lodise et al Vuagnat et al Association with other nephrotoxic drugs Aminoglycosides Piperacillin-Tazobactam? Diuretics?

10 No international guidelines concerning risk factors

11 Association with Piperacillin - Tazobactam Hammond et al. Clinical Infectious diseases 2017 Mechanism?

12 Vancomycin nephrotoxicity: mechanistic aspects

13 Vancomycin metabolism Histological findings (human) Small peptide (1.5 kda) Renal clearance Excreted unchanged in the urine Distribution volume (0,4-1L/kg) Protein binding 10-50% Few biopsies performed Filtered ++ Tubular secretion (renal OCT system) Tubular damage: ATN++ Interstitial nephritis Nakamura et al Codding et al Shah-Kahn et al. 2011

14 Vancomycin tubular toxicity: role of oxydative stress? 2016

15 The Case 56-year-old woman referred for Acute kidney injury History Diabetes mellitus Obesity (BMI = 40 kg/m2) and gastric bypass surgery Recent events Acute myelogenous leukemia (daunorubicin, cytarabin and gemtuzumab) Day 10: Pancytopénia and Fever without hemodynamic instability Normal renal function at baseline: plasma creatinin 41 µmol/l Treatment: Piperacillin-tazobactam 4g x 3/d IV Vancomycin: 1.5 g pulse + 3g/24h (continuous IV infusion) Luque et al. J Am Soc Nephrol 2017

16 The Case Kidney biopsy NaU 42 mmol/l, KU 28 mmol/l Protéinuria <0,1g/L No hematuria Normal ultrasound kidney examination

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18 Vancomycin intra-tubular detection Electronic microscopy and immunogold Luque et al. J Am Soc Nephrol 2017

19 The Case Infrared spectrometry

20 The Case Tubular obstruction: uromodulin reflux Vancomycin Uromodulin

21 Tubular vancomycin deposits Luque et al. J Am Soc Nephrol 2017

22 Retrospective analysis Tenon hospital ( ): ATN and vancomycin high trough levels Case Gender Age Initial clinical Context Circulatory Shock Serum creatinine At the time of the renal biopsy (mg/dl) Serum vancomycin Levels (mg/l) Vancomycin Therapy duration and dosage Time between vancomycin Withdrawal and renal biopsy (days) Other Nephrotoxic drugs* Dialysis Outcome A F 48 Meningitis No days (4g/d) 7 No No Recovery of the Renal function B M 45 Sepsis No days (NA) 7 No No Death C M 19 Septic Arthritis No Dialysis days (NA) 20 Gentamicin Yes Recovery of the Renal function D M 69 Septic Arthritis No 13 18,9 E M 46 Pneumonia No Dialysis 57,6 3 days (2g/d) 14 days (1,5g/d) 10 Gentamicin Yes Death 27 Gentamicin, Cisplatin Yes Death F F 73 Sepsis No ,5 8 days (2g/d) 17 Gentamicin No Recovery of the Renal function G F 69 Fever & neutropenia No days (NA) 15 No No Recovery of the Renal function H H 66 Septic Arthritis No days (NA) 10 No Yes Death I F 46 Fever & neutropenia No days (3g/d) 17 No No Recovery of the Renal function Luque et al. J Am Soc Nephrol 2017

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24 Vancomycin nephrotoxicity: the causality issue Experimental model of vancomycin nephrotoxicity in mice

25 m g /l INTRODUCTION NEPHROTOXICITY RISK FACTORS MECHANISMS CONCLUSIONS Experimental model Protocol: C57BL/6J mice (30 g) Intra-peritoneal vancomycin infusion Dosage: 25 mg at day 0 and day 1 Controls: PBS T a u x r é s id u e l V a n c o m y c in e J 2 Control Vanco Uromodulin 0 C T L V a n c o

26 Cast description Vancomycin Patient Mice

27 Intravital microscopy Methods: Vancomycin, BODIPY FL Conjugate (BODIPY FL Vancomycin) 100µg (bore-dipyrométhene)

28 Luque et al. J Am Soc Nephrol 2017

29 Luque et al. J Am Soc Nephrol 2017

30 Vancomycin-associated cast nephropathy

31 Vancomycin nephrotoxicity exists Population at risk: low GFR, obese, other nephrotoxic drugs, hypovolemia, high trough levels Mechanism: direct tubular toxicity and cast nephropathy Warning: trend to increase trough levels (30-40 mg/l )

32 ACKNOWLEDGEMENTS Urgences Néphrologiques et Transplantation Rénale Laurent Mesnard Kevin Louis Eric Rondeau Unité de recherche Inserm / UPMC UMR_S1155 Chantal Jouanneau Sandrine Placier Perrine Frère Emmanuel Esteve Sophie Vandermeersch Marie-Christine Verpont Anatomie et cytologie pathologiques David Buob / Isabelle Brocheriou / Patrice Callard Explorations fonctionnelles multidisciplinaires Vincent Frochot Michel Daudon Emmanuel Letavernier Laboratoire de Physique des Solides, U. Paris Sud Dominique Bazin Service d hématologie, hôpital Avicenne Alice Wolfromm Plate forme d'imagerie cellulaire Pitié-Salpêtrière Dominique Langui Aurélien Dauphin Néphrologie Hôpital Saint-Louis Anna Boueilh Maren Burbach Anatomie Pathologique Hôpital Saint-Louis Clément Gosset