Creatinine

 
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Physiology

Creatinine is produced as the result of normal muscle metabolism. Phosphocreatine, an energy-storing molecule in muscle, undergoes spontaneous cyclization to form creatine and inorganic phosphorous. Creatine then decomposes to creatinine. In health, production and excretion of creatinine are fairly constant in an individual animal, resulting in a high index of variability or low variation in an individual animal (Ruaux et al 2012, Hokamp and Nabity review 2016). An additional and relatively minor source is creatinine ingested during consumption of animal tissue and absorbed from the intestines. Creatinine is filtered freely through the glomerulus and is not reabsorbed in the tubules. Therefore, creatinine is considered a more reliable measure of GFR, compared to urea nitrogen, in most species, except for ferrets, as it is not influenced by diet or protein catabolism. Measurement of creatinine concentration in serum or plasma is included in chemistry profiles mainly to screen for decreased glomerular filtration rate (GFR).

Methodology

Technique used at Cornell

Blanked kinetic; Jaffe method

Procedure

In alkaline solution creatinine reacts with picric acid to form a yellow-orange complex. The concentration of creatinine is directly proportional to the rate of dye formation. Rate blanking is used to counter bilirubin interference and results are corrected for pseudo-creatinine chromogens.

Creatinine + picric acid  alkaline solution  > creatinine-picric acid complex

 

Units of measurement

Creatinine concentration is measured in mg/dL (conventional units) and μmol/L (SI unit). The conversion formula is shown below:

mg/dL x 88.4 = μmol/L

Sample considerations

Sample type

Serum, plasma, and urine

Anticoagulant

Heparin or EDTA

Stability

The stability of creatinine in human serum and plasma is as follows: 7 days at 15 – 25 °C or 2 – 8 °C, and 3 months at (-15)-(-25) °C (Roche product information sheet) 

Urine should be collected in the absence of any additives. If preservatives for other analytes are required only hydrochloric acid or boric acid may be used. The stability of creatinine levels in urine samples are as follows (per Roche product information sheet):

  • Stability in urine (without preservative): 2 days at 15 – 25 °C, 6 days at 2 – 8 °C, and 6 months at (-15)-(-25) °C.
  • Stability in urine (with preservative): 3 days at 15 – 25 °C, 8 days at 2 – 8 °C, and 3 weeks at (-15)-(-25) °C.

Interferences

These were obtained off the Roche product information sheet.

  • Lipemia: Severe lipemia (>1000 lipemia index)
  • Hemolysis: Will increase with severe hemolysis (>750 hemolysis index)
  • Icterus: Severe icterus (total bilirubin > 10 mg/dL or an icteric index > 10 units) may falsely decrease creatinine concentrations (this is based on data in humans and may not occur in animals or in every icteric animal). This effect can be minimized by using a reaction blank, as currently used in our assay.
  • Glucose: Can act as a chromogen in the picric-acid reaction, falsely increasing results.
  • Ketones: Acetoacetate (> 20 mmol/L) and β-hydroxybutyrate (>25 mmol/L)
  • Drugs: In serum and plasma samples, therapeutic levels of antibiotics containing cephalosporin result in significantly false-positive values. Cefoxitin causes spuriously high results.

Test interpretation

Increased creatinine concentration

  • Artifact: When measured by the Jaffe technique (which is based on color production and is used by the chemistry analyzer at Cornell University), both creatinine and non-creatinine chromogens react with the reagent. Non-creatinine chromogens include acetoacetate, glucose, vitamin C, uric acid, pyruvate, cephalosporins and amino acids. When present in high concentrations, these can falsely increase creatinine values.
  • Physiologic causes:
    • Physiologic: Creatinine is higher in premature and newborn foals (up to 8 mg/dL in newborn foals; this is thought to be due to defective placental transfer with the allantois containing more creatinine than plasma and should decline within 3-5 days) and heavily muscled horses (up to 2.5 mg/dL). Creatinine concentrations are higher in greyhounds (with a published upper reference limit of 2.0 mg/dL), presumably due to increased muscle mass (Dunlop et al 2011).
    • Increased production: A mild increase in creatinine (< 1 mg/dL) may be seen after ingestion of a recent meat meal.
  • Pathophysiologic causes
    • Decreased GFR:  Creatinine will increase with azotemia or decreased GFR that is due to prerenal, renal or post-renal causes. In ruminants and horses, creatinine is a better measure of GFR than urea nitrogen (due to gastrointestinal excretion and degradation of urea). Creatinine is a fairly insensitive marker of GFR, being increased with approximately a 1/3 reduction in renal function as measured by GFR (based on inulin clearance) and a 75% decrease in renal mass (Hokamp and Nabity review 2016). Less severe reductions in GFR may not manifest with a high creatinine. Because of the high index of individuality, monitoring changes in individual animals over time may be a more sensitive indicator of declining renal function (GFR) than comparing results to a previously established reference interval, which may be too broad to detect changes in individual animals unless there are substantial reductions in GFR. A change in creatinine of more than 0.3 mg/dL is considered support of declining GFR, but this change may be within the analytical variation of many machines used to measure creatinine (Hokamp and Nabity review 2016). Hence, as for all clinical pathologic values, results should always be interpreted in context of what is known or suspected to be occurring in the patient at hand.
    • Release from muscle: Although there have been reports of high creatinine due to release of creatine from muscle, studies have shown that acute myositis does not consistently increase creatinine. It is more likely that the creatinine is increased due to a renal azotemia from myoglobinuric nephrosis as a consequence of myoglobin release from severe myositis or myopathy.

Decreased creatinine concentration

  • Physiologic causes
    • Decreased muscle mass: Creatinine trends lower in small breeds of dogs, based on body weight (Misbach et al 2014, Hokamp and Nabity review 2016). Young dogs have lower creatinine than adult dogs, presumably due to lower muscle mass (Rosset et al 2012, Rørtveit et al 2015).
    • Increased GFR: This occurs during pregnancy (due to increased cardiac output).
  • Pathophysiologic causes
    • Decreased production: Loss of muscle mass from starvation or cachexia. Although creatinine is produced in the liver, low creatinine with liver insufficiency (e.g. portosystemic shunting) may be due to increased glomerular filtration rate (Deppe et al 1999) versus decreased creatine production in the liver.
    • Increased GFR: This occurs in animals with portosystemic shunts. Urea nitrogen is also frequently low from decreased liver synthesis of urea.

Discordant urea and creatinine

Urea and creatinine should always be interpreted together and in relation to the glomerular filtration rate. Below is a summary table of interpretations of different urea and creatinine combinations.

Interpretation of discordant urea nitrogen and creatinine values
Urea nitrogen Creatinine Interpretation
N / ↓ Early prerenal azotemia

Normal glomerular filtration rate (GFR) with ↑ urea nitrogen
High protein diet, upper gastrointestinal (GI) bleed
↓GFR with ↓ creatinine
Decreased muscle mass (cachexia)

 N / ↓  ↑ ↓ GFR with ↓ urea nitrogen
Hepatic failure, polyuria-polydipsia (in absence of chronic kidney disease), low protein diet, metabolism of urea nitrogen by GI flora (horses and cattle)
Normal GFR with ↑ creatinine
A normal finding in Greyhounds (increased muscle mass)
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