Purpose. The case of a patient who developed clinically relevant increases in serum creatinine (SCr) levels while receiving fenofibrate therapy is reported.
Summary. Fenofibrate therapy was initiated for a 60-year old Hispanic man with stage 4 chronic kidney disease (CKD) for the treatment of hypertriglyceridemia. Two weeks after taking 48 mg of fenofibrate daily, the patient’s SCr and blood urea nitrogen concentrations increased from 3.0 and 25 mg/dL, respectively, to 3.5 and 30 mg/dL, respectively. His estimated glomerular filtration rate (eGFR) had decreased from 24.8 to 17.9 mL/min/1.73 m2. One month after initiating fenofibrate, his SCr concentration had increased to 3.7 mg/dL, a 32% increase from baseline. Because of persistently high triglyceride concentrations (e.g., 402 mg/dL), the fenofibrate dosage was increased to 145 mg daily. The patient’s SCr concentration rose to 4.7 mg/dL (a 62% increase from baseline), and his eGFR was calculated as 13 mL/min/1.73 m2. The patient was referred by the nephrology service for vascular-access placement in preparation for hemodialysis. Four days after discontinuation of fenofibrate, the patient’s SCr concentration dropped to 3.3 mg/dL and returned to baseline approximately six weeks later, with an eGFR of 20.5 mL/min/1.73 m2. Preparation for hemodialysis was terminated, and the patient’s eGFR remained stable at 20.2 mL/min/1.73 m2 for the 12 months after fenofibrate discontinuation. A score of 4 on the Naranjo et al. probability scale indicated that there was a possible association between fenofibrate and renal dysfunction in this patient.
Conclusion. A 60-year-old patient developed renal impairment after receiving fenofibrate for the treatment of hypertriglyceridemia.
- Antilipemic agents
- Blood levels
- Glomerular filtration rate
- Kidney diseases
- Kidney failure
Fibric acid derivatives, such as fenofibrate, reduce triglyceride levels through activation of the peroxisome-proliferator activated receptor (PPAR) α. Activation of this receptor induces lipolysis and the elimination of triglycerides by activating lipoprotein lipase.1 Patients with chronic kidney disease (CKD) often have concomitant dyslipidemia and have a high risk of developing cardiovascular disease.2–5 The National Cholesterol Education Program Adult Treatment Panel III and the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines recommend either a fibrate or nicotinic acid, in addition to lifestyle changes, for the treatment of hypertriglyceridemia either as monotherapy or in combination with a statin.4,6
Reports of elevated serum creatinine (SCr) levels associated with fenofibrate have been published.7–13 These reports suggested that the risk of kidney dysfunction with fenofibrate therapy is higher in patients with CKD or patients who use concomitant drugs that affect renal hemodynamics (e.g., calcineurin inhibitors, diuretics). Previous data have been limited by failure to capture the time course of this adverse event, as most SCr values were analyzed as part of routine care several weeks to months after initiating fenofibrate therapy. Postulated mechanisms for fenofibrate-induced increases in SCr levels include increases in metabolic production of creatinine and altered renal hemodynamics.14,15
We report a case of a patient with underlying CKD who had a reversible increase in SCr values after treatment with fenofibrate for hypertriglyceridemia.
A 60-year-old, 115-kg, Hispanic man with hyperlipidemia, hypertension, type 2 diabetes mellitus, a history of renal cell carcinoma (status post right nephrectomy), and stage 4 CKD was given fenofibrate 48 mg orally daily for hypertriglyceridemia. The patient’s concomitant medications included simvastatin/ezetimibe 10 mg/40 mg orally daily, furosemide 120 mg orally every morning and 80 mg every evening, aspirin 81 mg orally daily, clonidine 0.2 mg orally twice daily, hydralazine 50 mg orally three times daily, amlodipine 10 mg orally daily, atenolol 25 mg orally daily, pantoprazole 40 mg orally daily, pioglitazone 30 mg orally daily, insulin glargine 60 units subcutaneously daily, insulin lispro 10 units subcutaneously with meals, and quinine sulfate orally 648 mg daily. The patient’s fasting cholesterol values while receiving therapy with simvastatin/ezetimibe were as follows: total cholesterol, 214 mg/dL; triglycerides, 422 mg/dL; and high-density lipoprotein cholesterol, 46 mg/dL; low-density lipoprotein cholesterol was not determined. His SCr and blood urea nitrogen (BUN) values were 3.0 and 25 mg/dL, respectively, at fenofibrate initiation. His baseline estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease equation was 24.8 mL/min/1.73 m2,16
Two weeks after taking 48 mg of fenofibrate daily, the patient’s SCr and BUN concentrations had increased to 3.5 and 30 mg/dL, respectively. His eGFR had declined to 19.2 mL/min/1.73 m2. One month after initiating fenofibrate, his SCr and BUN values had increased to 3.7 and 34 mg/dL, respectively. His eGFR had decreased to 17.9 mL/min/1.73 m2. Because the patient’s triglycerides had slightly decreased to 402 mg/dL, fenofibrate was increased to 145 mg daily. Approximately one month after this dosage increase, the patient’s BUN and SCr rose to 46 and 4.7 mg/dL, respectively. His eGFR was 13.6 mL/min/1.73 m2. Figure 1⇓ details the patient’s increases in SCr levels over approximately 10 weeks.
The patient was referred by the nephrology service for vascular-access placement in preparation for hemodialysis. Approximately two weeks later, his SCr concentration remained elevated (4.5 mg/dL), and the furosemide dosage was reduced to 40 mg twice daily. Fenofibrate was discontinued 14 days later, and the patient began low-dose niacin therapy for his elevated triglycerides. Four days after fenofibrate was discontinued, the patient’s SCr value decreased to 3.3 mg/dL and his eGFR increased to 20.5 mL/min/1.73 m2.
One month after fenofibrate discontinuation, the patient’s SCr measurement returned to near baseline (range, 3.2–3.4 mg/dL) and his appointment for vascular-access placement was canceled. Over the next 12 months, his eGFR remained stable at 20.2 mL/min/1.73 m2 after discontinuing fenofibrate, and there are no immediate plans to initiate hemodialysis. The patient had a Naranjo et al.17 probability score of 4, indicating a possible association between fenofibrate and renal dysfunction.
Renal dysfunction is a clinically important but under recognized adverse effect of fenofibrate therapy. Most data describing fenofibrate-associated renal dysfunction have come from published case reports, or case series.7–12 Mean increases in SCr ranged from 12% to 36% in these reports. Patients with preexisting CKD or other associated risk factors (e.g., receiving drugs that affect renal hemodynamics, status post kidney or liver transplant) had greater increases in SCr levels than did patients with normal renal function or mild renal dysfunction.
A large prospective study examined nearly 10,000 patients with diabetes mellitus receiving long-term fenofibrate therapy.13 The study excluded patients with preexisting renal dysfunction (defined as a baseline SCr concentration of >1.5 mg/dL). Despite the study participants’ inherent lower risk of nephrotoxicity, the median SCr values at the end of the study were significantly higher in the fenofibrate-treated group compared with patients receiving placebo (1.03 mg/dL versus 0.9 mg/dL, respectively) (p < 0.001).
Several mechanisms have been proposed to explain the rise in SCr levels associated with fenofibrate therapy. These can be broadly classified as (1) direct effects on skeletal muscle production of creatinine or (2) alterations in renal hemodynamics.
Hottelart et al.12 prospectively studied the effect of two weeks of fenofibrate therapy (200 mg daily) on 26 hyperlipidemic patients with either normal renal function or mild-to-moderate renal insufficiency (mean ± S.D. baseline creatinine clearance, 68 ± 8 mL/min). SCr concentration increased from 139 ± 8 mg/dL to 160 ± 10 mg/dL (p < 0.0001). GFR was measured in 13 patients by inulin steady-state clearance and remained essentially unchanged from baseline (68 ± 6 mL/min versus 67 ± 6 mL/min). In addition, renal plasma flow (assessed by p-aminohippuric acid clearance) was not affected by fenofibrate therapy, indicating a lack of effect on renal hemodynamics. The authors did not stratify patients with CKD to determine if their increases in SCr levels were greater than patients with normal renal function. The rise in SCr levels was associated with a rise in urinary creatinine excretion. The authors suggested that fenofibrate may cause an increase in SCr levels but not reduce renal function by increasing the metabolic production of creatinine from muscle.
Fibrates affect renal hemodynamics in rats by exerting a diuretic effect via binding to and activating PPARs. When PPARs are activated, the gene transcription of enzymes is altered, which may lead to increased endogenous inhibitors of sodium, potassium, and chloride transporters in the loop of Henle, resulting in increased intraluminal sodium concentrations and natriuresis.14 This action would not only result in afferent arteriole vasoconstriction but also activate the renin-angiotensin system, further adversely affecting renal hemodynamics. PPAR activation has also been found to downregulate the inducible cyclooxygenase-2 enzyme, which may impair generation of vasodilatory prostaglandins, resulting in afferent arteriole vasoconstriction.15 Thus, both perfusion to the kidneys and glomerular capillary pressure could be compromised.
Further support for fenofibrate-induced alteration of hemodynamics may be found in data demonstrating that fenofibrate increases plasma homocysteine.13,18,19 Reduced renal elimination of homocysteine and subsequent hyperhomocysteinemia are commonly found in patients with CKD. Elevated homocysteine levels correlate with increased SCr values; therefore, elevated homocysteine values may indicate reduced glomerular filtration.20
Our patient had several concomitant risk factors for hemodynamically induced renal dysfunction, including stage 4 CKD, high dosages of loop diuretics, and aspirin use. In contrast to Hottelart et al.’s12 findings, the results of two 24-hour urine collections did not demonstrate a parallel rise in urinary creatinine excretion after initiating fenofibrate (data not shown). Our patient’s eGFR rapidly deteriorated, with a parallel rise in BUN values with low-dosage fenofibrate, making a hemodynamic mechanism more plausible. His renal function rapidly returned to baseline after discontinuation of fenofibrate. To our knowledge, this is the first report to demonstrate that fenofibrate-induced renal dysfunction occurs rapidly and may be dosage related.
The consequences of fenofibrate-induced renal dysfunction can be clinically significant but appear to be rapidly reversible after withdrawal of the drug. The manufacturer’s prescribing information advises to minimize the dosage of fenofibrate in patients with severe renal insufficiency (creatinine clearance of <50 mL/min) based on data demonstrating reduced clearance in this population.1 Abnormal kidney function is listed as an adverse reaction to fenofibrate; however, the package insert provides no information about monitoring kidney function after initiating fenofibrate therapy. We recommend obtaining SCr and BUN levels and calculating the eGFR before and one week after fenofibrate initiation or after dosage increases in high-risk patients.
A 60-year-old patient developed renal impairment after receiving fenofibrate for the treatment of hypertriglyceridemia.
- Copyright © 2008. American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/04/0602-1242$06.00