An Increase in Serum Creatinine after Initiation of Fenofibrate in an HIV-Infected Individual: A Case Report and Review of the Literature

Abstract

Hypertriglyceridemia is common among patients infected with HIV and often requires treatment with a triglyceride-lowering medication, such as fenofibrate. Studies have shown that fenofibrate has the potential to increase serum creatinine, a phenomenon that seems to occur more in patients with baseline renal dysfunction or who are on medications that can affect renal hemodynamics. HIV-infected individuals are at an increased risk of developing renal problems and may be a target population for fenofibrate-induced increases in serum creatinine. The purpose of this report is to describe a case of an HIV-infected individual who experienced a considerable increase in serum creatinine after initiating fenofibrate, and to highlight this underreported yet important adverse effect. Additionally, we discuss the postulated mechanisms, relevant literature among HIV noninfected individuals, and potential risk factors.

Introduction

Hyperlipidemia, particularly hypertriglyceridemia, is common in patients with HIV infection for several possible reasons. Studies have shown antiretroviral therapy (ART), most notably the HIV protease inhibitors (PIs), to be associated with hyper-triglyceridemia.^1–7 It is estimated that hypertriglyceridemia occurs in >50% of patients taking PIs after 2 years of therapy, and that the risk increases with longer duration of therapy.⁸ In addition, HIV infection alone has been shown to be accompanied by increased plasma triglyceride levels, even in individuals who are not on ART.^9–12 One case-control study showed that HIV-infected individuals started off with increased triglycerides, as compared to age- and sex-matched sero-negative volunteers, and that the introduction of PIs resulted in an average triglyceride increase of 146% (P < .0001).¹³ This is a clinically significant finding because, based on the Third Report of the National Cholesterol Education Program (NCEP), elevated triglycerides have been shown to be an independent cardiovascular disease risk factor.¹⁴

When triglycerides are very high (defined as >500 mg/dL), triglyceride-lowering drugs (such as a fibrate or nicotinic acid) are indicated.¹⁴ Fibrates (such as fenofibrate and gemfibrozil) effectively reduce triglycerides,^12–16 are generally well tolerated, and require little laboratory monitoring. For HIV-infected individuals who may be taking numerous medications, fenofibrate is a favorable choice because it can be dosed once daily.¹⁷ However, a less well-known adverse effect of fenofibrate therapy is an elevation in serum creatinine (Scr). Fenofibrate is contraindicated in severe renal dysfunction and should be dose-adjusted according to specific product labeling with regard to clearance creatinine.

Given the aging HIV-positive population, kidney disease has emerged as a significant cause of morbidity and mortality.¹⁸ Additionally, despite the decreasing incidence of kidney disease attributed to HIV-associated nephropathy (HIVAN) due to widespread use of ART, end-stage renal disease (ESRD) related to HIV infection continues to rise.^19,20 Therefore, it is essential to identify medications with a potential for affecting renal function and to monitor Scr after their initiation.²¹

Due to the high incidence of hypertriglyceridemia necessitating the use of fibrates and the increased risk for declining renal function in HIV-infected patients, knowledge of the fenofibrate-induced Scr elevation is of paramount importance. However, because of underreporting and lack of research in this area, many HIV care providers may be unaware of this important issue. The purpose of this case report is to highlight a case in which fenofibrate may have resulted in an increase in Scr, and to discuss the literature regarding this adverse effect.

Case Presentation

We report a case of a 52-year-old HIV-infected Philipino man, with a body mass index (BMI) of 23 kg/m², with hypertension, chronic hepatitis C, and dyslipidemia, who was started on fenofibrate for hypertriglyceridemia. Prior to initiating fenofibrate, the patient’s baseline Scr was 1.59 mg/dL and had been averaging 1.47 mg/dL from the last 8 routine checks over a period of 11 months. His estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease (MDRD)²² equation was 46 mL/min per 1.73 m². The patient had developed acute kidney injury 2 years prior during a hospitalization for pneumonia and had experienced a decrease in renal function since that time. His triglyceride level at baseline was 867 mg/dL, which was confirmed with a repeat test 2 days later. His fasting high-density lipoprotein cholesterol was 29 mg/dL and a direct measure of his low-density lipoprotein cholesterol was 70 mg/dL. Due to a very high triglyceride level and an eGFR close to the dose-adjusting limit (ie, eGFR <50 mL/min per 1.73 m²), fenofibrate 160 mg once daily was initiated. His medications at the time were lisinopril-hydrochlorothiazide (10 mg–12.5 mg daily), norvir (100 mg daily), atazanavir (300 mg daily), fixed-dose combination of abacavir 600 mg and lamivudine 300 mg (1 tablet daily), and dapsone (100 mg daily). He had taken tenofovir, in the fixed-dose combination with emtricitabine, for 3.5years, which was discontinued 3 months prior due to concerns about changing renal function. The patient was not taking any over-the-counter medications or herbal supplements. His Scr and other laboratory values had been stable on lisinopril-hydrochlorothiazide for at least 2 months. At the time of starting fenofibrate, CD4⁺ cell count was 234 cells/mm³, HIV RNA had been <75 copies/mL for at least 3 years, and blood pressure was well controlled (averaging less than 130/80mmHg).

Approximately 4 weeks after starting fenofibrate, the patient’s Scr increased to 1.77 mg/dL (eGFR 41 mL/min per 1.73 m²). Fenofibrate was continued, as it had considerably lowered his triglyceride level to 211 mg/dL. In addition, it was uncertain if the fenofibrate had been responsible for the increase in Scr. However, 2 weeks later, when the patient’s Scr had further increased to 1.83 mg/dL (eGFR 39 mL/min per 1.73 m²), fenofibrate was discontinued. Two weeks after discontinuation of fenofibrate, the patient’s Scr decreased to 1.63 mg/dL (eGFR 45 mL/min per 1.73 m²) and his triglyceride level returned to 564 mg/dL. Five months after discontinuation of fenofibrate, the patient’s Scr had returned to its baseline level of 1.59 mg/dL (eGFR 46 ml/min per 1.73 m²).

Discussion

Several theories have been described in the literature in an attempt to explain the mechanism of fenofibrate-induced increases in Scr. One proposed mechanism is an increase in the metabolic production of creatinine from muscle,²³ which would not reflect a true deterioration of renal function. In other words, despite an elevation in Scr, glomerular filtration rate (GFR) is unchanged. Trimethoprim, cimetidine, pyrimethamine, and salicylates exhibit a similar phenomenon by increasing Scr through inhibition of creatinine secretion by the proximal tubule without affecting GFR.²⁴ An opposing theory is that fenofibrate impairs the generation of vasodilatory prostaglandins through activation of peroxisome proliferator-activated receptors (PPARs), thus leading to afferent arteriole vasoconstriction. Peroxisome proliferator-activated receptors are a group of nuclear receptor proteins that function as transcription factors regulating the expression of various genes.²⁵ Peroxisome proliferator-activated receptor activation in the kidney may also result in natriuresis, which would result in the activation of the renin-angiotensin system.²⁶ According to this theory, the use of fenofibrate would result in a true decline in renal function, as evident by a decrease in GFR.

In HIV-negative individuals, this phenomenon has been described in the literature.^27–36 Most recently, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study showed that mean Scr levels increased from 0.93 mg/dL to 1.0 mg/dL with the use of fenofibrate versus placebo within the first year of the study and remained stable thereafter. In this study, fenofibrate was discontinued by 66 participants (2.4%) as compared to 30 (1.1%) in the placebo group because of a decrease in the eGFR below 30 mL/min per 1.73 m². At the last clinic visit, after a mean period of 4.7 years, 440 patients (15.9%) in the fenofibrate arm and 194 (7.0%) in the placebo arm were receiving a reduced dose of either fenofibrate or placebo because of a decreased eGFR. Despite these changes, no significant difference in the incidence of hemodialysis or ESRD was found (75 events in the fenofibrate group versus 77 events in the placebo group).²⁹ Similarly, increases in Scr were also seen in the FIELD study, which returned to baseline level within 8 weeks of fenofibrate discontinuation.²⁷ It should be noted that alteration in renal function due to fenofibrate was not the primary outcome of either study and in both studies fenofibrate was either discontinued or dose-reduced at the onset of clinically significant renal function changes.

Notably, many case reports suggest that the risk associated with fenofibrate and increasing Scr is more prominent in patients with underlying kidney dysfunction or patients taking medications that can alter renal hemodynamics (such as angiotensin-converting enzyme inhibitors [ACE-inhibitors], angiotensin receptor blockers [ARBs], nonsteroidal anti-inflammatory drugs [NSAIDs], calcineurin inhibitors, etc).^27–36 Medications altering renal hemodynamics can do so by decreasing GFR through either direct or indirect vasoconstriction of the afferent arteriole or vasodilation of the efferent arteriole.

In the HIV-positive population, the literature associating fenofibrate with an increase in Scr is far less prolific. It seems that HIV-infected individuals, however, would be particularly susceptible to this adverse effect given their increased risk for declining renal function. Important risk factors for chronic kidney disease (CKD) in HIV are black race, diabetes, hypertension, low CD4⁺ cell count, high HIV viral load, hepatitis C coinfection, AIDS, and antiretroviral agents with nephrotoxic potential.^37–40 Recently, Mocroft et al reported data from the EuroSIDA cohort study and found that among 6874 patients, during a median follow-up of 3.7 years, 225 (3.3%) developed CKD.²¹ In addition to the traditional risk factors noted previously, they found cumulative exposure to atazanavir, tenofovir, and indinavir increased risk of CKD (increased relative risk per year of use: 22%, 16%, and 11%, respectively). Atazanavir in combination with tenofovir increased risk by 41% per year of use. The risk associated with tenofovir remained elevated approximately 1 year after its discontinuation. Importantly, the progression of declining renal function may not be readily apparent through laboratory testing. One study looking at a cohort of ART-experienced patients with advanced HIV disease found a high prevalence of subclinical renal pathology which would not have been predicted using the current diagnostic criteria for CKD.⁴¹ It was only through postmortem histopathologic examination that more than half of the patients were revealed to be at risk for early kidney disease.

In our case report, HIV infection and the use of PIs likely contributed to triglyceride elevations necessitating the use of triglyceride-lowering therapy. Fenofibrate was chosen due to the fact that it is well tolerated and has a low pill burden. However, given the substantial Scr increase after fenofibrate initiation, based on the Naranjo Scale,⁴² this medication was possibly associated with the increase in Scr (estimated likelihood = 4). Moreover, the patient had several risk factors that increased his likelihood of experiencing such an adverse effect, including past history of acute kidney injury, hepatitis C coinfection, low CD4⁺ cell count, hypertension, use of tenofovir within 4 months, and current use of lisinopril and atazanvir boosted with ritonavir.

Based on prior reports of this adverse effect in HIV-negative participants and given our case report in an HIV-positive individual, we believe that monitoring Scr following the initiation of fenofibrate is essential. Close monitoring of Scr is especially critical for HIV-infected patients with a history of acute kidney injury or renal dysfunction, those on medications that can alter renal hemodynamics (such as ACE-inhibitors, ARBs, NSAIDS), those on antiretroviral medications that have been associated with changes in renal function (such as tenofovir), individuals with low CD4⁺ cell counts, and those with other comorbidities (such as hepatitis C, hypertension, etc). We suggest checking Scr and calculating eGFR within approximately 2 to 3 weeks of starting fenofibrate therapy and then as needed based on renal function or with routine HIV laboratory testing.

In conclusion, hypertriglyceridemia is common in patients with HIV infection due to ART or the infection itself. In addition, HIV-positive individuals are at an increased risk for kidney disease. Fenofibrate can be used successfully to lower triglycerides but may also alter Scr. At this time, it is unknown whether this adverse effect can result in future morbidity; thus, it is essential that it be acknowledged and monitored. HIV health care providers should be aware of the fact that fenofibrate may result in an increase in Scr, should monitor Scr, and exercise their best judgment to determine if and when this medication needs to be discontinued.