The kidney plays a major role in clearance of drugs and their metabolites from the body. Renal clearance occurs through glomeruli filtration, renal tubular secretion, and renal tubular reabsorption. Drugs may be totally or partially cleared by the kidneys. As renal function declines, clearance of drugs primarily renally eliminated declines in a proportional manner. This is reflected by an increase in drug levels and half-life, which may lead to toxicity. Monitoring of renal function allows for appropriate modification of drug regimens to prevent toxicity.
Creatinine clearance provides an estimation of glomerular filtration rate (GFR). Creatine is produced by the liver, pancreas, and kidneys. It is a high energy substrate used by muscles. Creatinine is the metabolic by-product which is produced at constant rate of 1.5-2% of the total pool.
Creatinine production is determined by lean muscle mass and is therefore impacted by sex and age. Creatinine is distributed into total body water with a volume of distribution 0.6 L/kg. Female production is approximately 85% of males. Creatinine production declines throughout life as muscle mass declines. The rate of creatinine production is constant for an individual over a finite time span.
Creatinine is mainly filtered in the glomerulus, with a small proportion excreted by active tubular secretion. Creatinine clearance is useful for estimating GFR.
As renal function declines, tubular secretion accounts for a greater percentage of creatinine clearance. Tubular secretion is inhibited by numerous medications including:
Cimetidine 800 mg Q12H may be used to inhibit tubular secretion to obtain a more accurate estimation of creatinine clearance.
Medications may interfere with creatinine assays:
Accuracy of calculations may be impacted by conditions affecting muscle mass or muscle function: amputations, spinal cord injury, liver disease, malnourishment, and obesity.
Important: Bayesian dosing methods are not recommended in patients whose production of creatinine is significantly lower than the model's studied population as mean pharmacokinetic parameters will be significantly different. The predicted levels will be much lower than actual levels and erroneous dosing recommendations will be made. Attention should be focused on actual levels achieved and not on the predicted levels.
Adjustment of ideal or lean body weight by percentage weight lost:
Severe liver dysfunction decreases serum creatinine likely due to low muscle mass, decreased liver function, protein malnutrition, and proportionally increased secretion of creatinine, especially at low GFR. Creatinine-based equations for glomerular filtration rate estimation have been proven to be inaccurate for cirrhotic patients. Specific equations or correction factors for creatinine based GFR are unavailable for liver dysfunction.
Elevation in serum creatinine in cirrhosis is indicative of the presence of either an acute kidney injury (AKI) or chronic kidney disease (CKD). If the BUN/SCr ratio is elevated and total bilirubin is elevated, the serum creatinine may be falsely low and conservative dosing and therapeutic drug monitoring should be more aggressive.
It is common to observe patients being overdosed when healthcare providers failed to associate these values with low creatinine production and erroneous creatinine clearance calculations.
Rounding up of low serum creatinine values to 0.7 mg/dl in non-spinal cord injury patients and 0.5 mg/dl in spinal cord injury is recommended to prevent under/over dosing, along with serum level monitoring as applicable.
Serum Creatinine (mg/ml) = Rate of Creatinine Production (mg/min) / Clearance of Creatinine (ml/min)
Clearance of Creatinine (ml/min) = Rate of Creatinine Production (mg/min) / Serum Creatinine (mg/ml)
Weight is ideal body weight or actual weight (ABW) if lower than ideal for non-obese.
Weight = IBW + 0.4 × (ABWkg - IBWkg) for obese
This is the most accurate method for calculation of creatinine clearance after changes in renal function and is incorporated in most dosing tools on this site.
Creatinine Concentrations, Comparison of Multiple Methods. MSS Chow Drug Intelligence and Clinical Pharmacy 1985;19:385-90
Serum Creatinine2 (mg/L) = Serum Creatinine1 (mg/L) × e(-K×T) + Rate of Production × (1 - e(-K×T))
K is found through an iterative data fitting method or by using the Solver add-in in Excel
CrCl (L/hr) = K1/hr × VdL
CrCl (ml/min) = CrClL/hr × 1000 ml/L / 60 minutes/hr
This equation accounts for the elimination of creatinine already present and the fraction of steady state achieved during the time between the creatinines.
Males: CrClml/min = {[(293 - 2.03 × Ageyears) × (1.035 - 0.01685 × (SCr1 + SCr2))] + [49 × (SCr1 - SCr2) / TimeChange]} / (SCr1 + SCr2)
Females: CrClml/min = 0.86 × above
CrCl (ml/min) = [[(Production of Creatininemg/day) - [(SCr2 - SCr1) × 0.6 × Weight) / Timeday) × 10 dl/L]] / (SCr2 × 10 dl/L)] × (1000 ml/L / 1440 min/day)