Mechanisms Underpinning Increased Plasma Creatinine Levels in Patients Receiving Vemurafenib for Advanced Melanoma

<div><p>Context</p><p>Serum creatinine has been reported to increase in patients receiving Vemurafenib, yet neither the prevalence nor the mechanism of this adverse event are known.</p><p>Objective</p><p>We aimed to evaluate the frequency and the mechanisms of increases in plasma creatinine level in patients receiving Vemurafenib for advanced melanoma.</p><p>Methods</p><p>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.</p><p>Results</p><p>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.</p><p>Conclusion</p><p>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.</p></div

Main clinical and biological data of the 70 patients at baseline and during the treatment.

<p>Main clinical and biological data of the 70 patients at baseline and during the treatment.</p

Flow-chart of patients included.

<p>Flow-chart of patients included.</p

Renal handling of creatinine before and after introduction of Vemurafenib.

<p>For each patient and each visit, the black part of the bar represents GFR (urinary clearance of ⁵¹CrEDTA) and the grey part of the bar represents the proportion of creatinine clearance due to secretion, the whole bar representing overall urinary clearance of creatinine. For each patient, the proportion of clearance of creatinine due to its secretion decreased under Vemurafinib treatment by 55, 43 and 81% for patients 1, 2 and 3 respectively.</p

Renal function before and after introduction of Vemurafenib.

<p>Renal function before and after introduction of Vemurafenib.</p