Drugs that elevate the serum creatinine concentration

INTRODUCTION — An elevation in the serum creatinine concentration (SCr) usually reflects a reduction in the glomerular filtration rate and is associated with a concomitant rise in the blood urea nitrogen (BUN). (See "Assessment of kidney function".)

There are, however, a variety of settings in which the SCr can increase acutely independent of a decrease in the glomerular filtration rate (GFR), and, therefore, in which there is no true change in overall kidney function. This may be due to one of three factors: decreased creatinine secretion, interference with the serum assay, or enhanced creatinine production.

Thus, in patients taking one of the drugs described below, an elevation of creatinine without a concomitant elevation of BUN does not likely reflect a true decrease in GFR.

DECREASED SECRETION — In normal subjects, approximately 15 percent of the urinary creatinine is derived from secretion in the proximal tubule. This value can rise to as high as 50 percent in patients with advanced kidney disease and accounts for the overestimation of the true glomerular filtration rate (GFR) by the creatinine clearance [1]. (See "Calculation of the creatinine clearance".)

Creatinine is an organic cation in the physiologic pH range and is secreted by the organic cation secretory pump and the solute carrier family 47 member 1 (SLC47A1) transporter (also known as multidrug and toxin extrusion 1, or MATE1), and secretion can be inhibited by other organic cations. Certain drugs can interfere with creatinine secretion via these proteins and therefore result in a reversible rise in the SCr. The magnitude of the rise depends upon the proportion of creatinine that is secreted (versus filtered) as well as the specific drug that is inhibiting transport. Commonly used drugs that elevate the serum creatinine include:

●The antimicrobial trimethoprim (which is most often given in combination with sulfamethoxazole) [2].

●The antiarrhythmic drug dronedarone (which is used in some patients with atrial fibrillation) [3].

●The H₂ blocker, cimetidine [4,5]. Famotidine, which is another commonly used H₂ blocker, has a much less prominent effect on creatinine handling [5].

The effect of cimetidine has been used clinically to improve the accuracy of the creatinine clearance [4,6,7]. By competitively inhibiting creatinine secretion, the creatinine clearance becomes a more accurate measure of the true glomerular filtration rate. (See "Calculation of the creatinine clearance".)

●Dolutegravir and cobicistat, which are two drugs used in the treatment of HIV, can increase serum creatinine and decrease estimated GFR due to decreases in creatinine secretion [8-11]. Dolutegravir blocks the uptake of creatinine from the blood by inhibiting an organic cation transporter, whereas cobicistat affects the efflux of creatinine by inhibiting SLC47A1 [7]. Increases in SCr occur within the first four weeks of therapy and plateaued thereafter.

●The poly-ADP ribose polymerase (PARP) inhibitors such as olaparib and rucaparib, which are used to treat certain types of cancer, may inhibit proximal tubule transporters, including organic cation transporters and SLC47A1, thereby reducing creatinine secretion [12,13].

●Tyrosine kinase inhibitors, such as imatinib, bosutinib, sorafenib, and sunitinib, crizotinib, gefitinib, and pazopanib may inhibit SLC47A1-mediated secretion of creatinine and thereby elevated the SCr [14-16].

●The antiparasitic drug pyrimethamine, which is used as a second-line drug for prophylaxis or treatment of toxoplasmosis and Pneumocystis jirovecii pneumonia, interferes with tubular creatinine secretion [17].

INTERFERENCE WITH THE SERUM ASSAY — Serum creatinine is most often measured by the alkaline picrate method. This colorimetric assay can recognize other compounds as creatinine chromogens, particularly acetoacetate in diabetic ketoacidosis [18]. In this setting, the SCr can rise by 0.5 to 2 mg/dL or more (44 to 176 micromol/L), a change that is rapidly reversed with insulin therapy. Cefoxitin and flucytosine are other drugs that can produce a similar effect [19,20].

The Ektachem (Eastman Kodak Co., Rochester, New York) method, using the enzyme creatinine iminohydrolase, and the creatinine PAP method (Boehringer Mannheim, Mannheim, Germany), using the enzymes creatininase, creatinase, and sarcosine oxidase, yield creatinine values comparable to those obtained using the kinetic alkaline picrate method. In general, these methods appear to have less interferences than the alkaline picrate methods, but there are reports of interfering substances [21]. As examples:

●The antifungal agent flucytosine interferes with the Ektachem measurement; it may increase the value by as much as 60 percent [22-24].

●A proline stabilizer infused with intravenous immune globulin (IVIG) therapy produced increased serum creatinine in one report [25]. The elevated creatinine measurement was due to positive interference in the enzymatic creatinine assay, likely due to the activity of sarcosine oxidase on proline.

It seems likely in the future that more specific assays for creatinine will eliminate the problem of drug interference. One possible method is the use of an artificial receptor that is specific for creatinine and that undergoes a color change when creatinine is bound [26].

ENHANCED CREATININE PRODUCTION — The SCr varies during the day, rising by as much as 0.5 to 1 mg/dL (44 to 88 micromol/L) after a large cooked meat meal (since muscle contains creatine, which is converted to creatinine by the heat from cooking) and then returning slowly to the baseline level [27].

It has also been suggested that the SCr rises more rapidly with rhabdomyolysis (up to 2.5 mg/dL or 220 micromol/L per day) than with other causes of acute kidney injury [28]. Release of preformed creatinine from injured muscle and/or release of creatine that is then converted into creatinine in the extracellular fluid have been proposed to explain this finding. However, neither of these mechanisms appear to account for the increase in the SCr [29]. An alternative explanation is that rhabdomyolysis often affects men with a high muscle mass and a higher rate of creatinine production than seen in frequently ill patients with other forms of acute kidney injury [28].

Creatine supplements are increasingly used in health and disease. For most people, this will not lead to increases in serum creatinine levels (or declines in estimated glomerular filtration rate [GFR]). One randomized control trial of patients with diabetes showed no effect on GFR measured using (51)Cr-EDTA clearance [30], despite higher muscle phosphoryl creatine.

SUMMARY

●A variety of drugs can affect the serum creatinine level. There are two primary mechanisms for this. The drug may compete with the secretion of creatinine at the level of the kidney tubule or may interfere with the assay. Increased intake of creatine and creatinine may also elevate the level of creatinine in the blood, independent of glomerular filtration rate. (See 'Decreased secretion' above and 'Interference with the serum assay' above and 'Enhanced creatinine production' above.)