Fibrates and increase in plasma creatinine

• a moderate and reversible rise in plasma creatinine term levels is a common side effect of fibrates
  • increased creatininemia has been reported in studies with fenofibrate, bezafibrate and and ciprofibrate (1)
    • increased creatinine levels were observed in patients with normal as well as in those with impaired basal renal function, and in renal transplanted as well as in non-transplanted patients
    • the ability of gemfibrozil to increase creatininemia is extensively debated and for some authors, gemfibrozil would present a better safety profile relative to fenofibrate or clofibrate in this respect (2)
    • unknown whether the effect on plasma creatinine results from a PPAR alpha-related or unrelated effect
      • several hypotheses have been proposed regarding the mechanism underlying fibrate-induced increase in serum creatinine
        • it has been reported that there is a parallel increase in plasma urea leading to the hypothesis that the rise in creatininemia reflected an alteration of renal function (3)
          • it has been proposed that an altered renal function might be related to a PPAR alpha-mediated down-regulation of cyclooxygenase (COX-2) in the kidneys and resulting decreased synthesis of vasodilating prostaglandins
          • in support of this hypothesis, clofibrate and ciprofibrate, but not gemfibrozil inhibited the production of vasodilatory prostaglandins
        • another hypothesis is that the increase in serum creatinine is based on changes of renal hemodynamics (4)
          • proposed that fibrates induce natriuresis, leading to volume depletion and subsequently to increased urea and creatinine
            • however this theory has been challenged by those who argue that if this mechanism would be real, a disproportionate increase in serum urea compared to serum creatinine would be expected which has not been observed in most of the published studies
        • some reports suggest that fibrate-induced increase in serum creatinine does not reflect a deterioration in renal function since other more precise estimators of GFR remain unaffected
          • the authors of these studies proposed that fibrate raise creatininemia by increasing net daily production of creatinine, presumably from muscle origin (4,5)
  • although the role of PPAR alpha activation in the mechanism of fibrate-induced rise in creatininemia remains to be clearly understood, the potential deleterious effects of some, but not all, fibrateson renal function suggest that their clinical use in patients at risk for renal insufficiency has to be carefully considered
  • medical authorities also recommend frequent assessment of plasma urea and creatinine levels in normal patients on fibrates (1)

Reference:

• 1. Rubestrunk A et al. Safety issues and prospects for future generations of PPAR modulators Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 2007; 1771 (8): 1065-1081.
• 2. Broeders N et al. Fibrate term-induced increase in blood urea and creatinine: is gemfibrozil the only innocuous agent?.Nephrol. Dial. Transplant. 2000;15: 1993-1999.
• 3. Lipscombe et al. Deterioration in renal function associated with previous termfibratenext term therapy. Clin. Nephrol. 2001;55: 39-44.
• 4. Hottelart C et al. Fenofibrate increases blood creatinine, but does not change the glomerular filtration rate in patients with mild renal insufficiency. Nephrologie 1999;20 (1999): 41-44.
• 5. Hottelart C et al. Fenofibrate increases creatininemia by increasing metabolic production of creatinine. Nephron 2002; 92: 536-541.