title: Mechanisms Underpinning Increased Plasma Creatinine Levels in Patients Receiving Vemurafenib for Advanced Melanoma.
abstract: BACKGROUND
  Serum creatinine has been reported to increase in patients receiving Vemurafenib, yet neither the prevalence nor the mechanism of this adverse event are known.
  
  
  OBJECTIVE
  We aimed to evaluate the frequency and the mechanisms of increases in plasma creatinine level in patients receiving Vemurafenib for advanced melanoma.
  
  
  METHODS
  We performed a retrospective monocentric study including consecutive patients treated with Vemurafenib for an advanced melanoma. We collected clinical and biological data concerning renal function before introduction of Vemurafenib and in the course of monthly follow-up visits from March 2013 to December 2014. Cystatin C-derived glomerular filtration rate was evaluated before and after Vemurafenib initiation, as increase in serum cystatin C is specific to a decrease in the glomerular filtration rate. We also performed thorough renal explorations in 3 patients, with measurement of tubular secretion of creatinine before and after Vemurafenib initiation and a renal biopsy in 2 patients.
  
  
  RESULTS
  70 patients were included: 97% of them displayed an immediate, and thereafter stable, increase in creatinine (+22.8%) after Vemurafenib initiation. In 44/52 patients in whom Vemurafenib was discontinued, creatinine levels returned to baseline. Serum cystatin C increased, although proportionally less than serum creatinine, showing that creatinine increase under vemurafenib was indeed partly due to a renal function impairment. In addition, renal explorations demonstrated that Vemurafenib induced an inhibition of creatinine tubular secretion.
  
  
  CONCLUSIONS
  Thus, Vemurafenib induces a dual mechanism of increase in plasma creatinine with both an inhibition of creatinine tubular secretion and slight renal function impairment. However, this side effect is mostly reversible when Vemurafenib is discontinued, and should not lead physicians to discontinue the treatment if it is effective.
authors.affiliation: Dermatology Department, Hôpital Saint-Louis, Assistance-Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hurabielle
authors.affiliation: Nephrology Department, Hôpital Saint-Louis, Assistance-Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Evangéline
authors.initials: E
authors.lastname: Pillebout
authors.affiliation: Physiology Department, DHU Fire, Hôpital Bichat, Assistance-Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stehlé
authors.affiliation: Dermatology Department, Hôpital Saint-Louis, Assistance-Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Pagès
authors.affiliation: Dermatology Department, Hôpital Saint-Louis, Assistance-Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Roux
authors.affiliation: Dermatology Department, Hôpital Saint-Louis, Assistance-Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Schneider
authors.affiliation: Biostatistic Department, Hôpital Saint-Louis, Assistance-Publique-Hôpitaux de Paris, ECSTRA Team, Inserm UMR-1153, Université Paris 7 Diderot, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevret
authors.affiliation: Biostatistic Department, Hôpital Saint-Louis, Assistance-Publique-Hôpitaux de Paris, ECSTRA Team, Inserm UMR-1153, Université Paris 7 Diderot, Paris, France.
authors.forename: Cendrine
authors.initials: C
authors.lastname: Chaffaut
authors.affiliation: Biochemistry Department, Hôpital Bichat, Assistance-Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Boutten
authors.affiliation: Pharmacology and Genetic Department, Hôpital Saint-Louis, Assistance-Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Mourah
authors.affiliation: Dermatology Department, Hôpital Saint-Louis, Assistance-Publique-Hôpitaux de Paris, Paris, France.|Inserm Unit 976, Hôpital Saint-Louis, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Basset-Seguin
authors.affiliation: Physiology Department, DHU Fire, Hôpital Bichat, Assistance-Publique-Hôpitaux de Paris, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Vidal-Petiot
authors.affiliation: Dermatology Department, Hôpital Saint-Louis, Assistance-Publique-Hôpitaux de Paris, Paris, France.|Inserm Unit 976, Hôpital Saint-Louis, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Céleste
authors.initials: C
authors.lastname: Lebbé
authors.affiliation: Physiology Department, DHU Fire, Hôpital Bichat, Assistance-Publique-Hôpitaux de Paris, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Flamant
mesh_terms: D000368:Aged; D003404:Creatinine / Q000097:blood*; D055316:Cystatin C / Q000097:blood; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D008545:Melanoma / Q000097:blood* / Q000188:drug therapy* / Q000503:physiopathology; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D051437:Renal Insufficiency / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology; D012189:Retrospective Studies; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D000077484:Vemurafenib
chemical_list: D055316:Cystatin C; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D003404:Creatinine