Creatinine: Reference Range, Interpretation, Collection and Panels (2024)

Description

Creatinine is critically important in assessing renal function because it has several interesting properties. In blood, it is a marker of glomerular filtration rate; in urine, it can remove the need for 24-hour collections for many analytes or be used as a quality assurance tool to assess the accuracy of a 24-hour collection.

Creatinine forms at a relatively constant rate in muscle. Chemically, it is the anhydride (dehydration product) of creatine; once formed, it cannot be converted back into creatine. Therefore, the amount of creatinine formed on a daily basis is related to muscle mass, which varies with ethnicity, age, and gender.

Creatinine is freely filtered through the glomerulus and is not appreciably reabsorbed or secreted by the renal tubules. (In advanced renal failure, secretion, although the absolute amount may be minor, may represent a significant fraction of total excretion.) As a result, the serum concentration of creatinine represents a balance between its production (related to muscle mass) and the GFR. For any given patient, the serum creatinine is constant, so long as muscle mass remains unchanging and GFR is constant. To summarize, the clearance of creatinine, unlike that of most analytes, is an excellent surrogate for GFR. ^[9]

Put differently, if the GFR decreases and production (and daily excretion) remains constant, the serum concentration has to increase. (The serum concentration increases until the concentration is such that, when multiplied by the GFR, the product matches the daily excretion.) Thus, if one loses half of one’s renal function, the creatinine doubles; a creatinine increase from 1.0 to 2.0 represents the same decrement in renal function as a creatinine increase from 2.0 to 4.0 or 4.0 to 8.0, as reflected in the graph below.

Indications/applications

Because different individuals have different muscle masses, using a single reference interval can be misleading. A serum creatinine of 1.0 in a 50-year-old white woman represents a significantly reduced GFR; the same value in a 25-year-old black male represents a normal GFR.

Determining GFR accurately requires onerous methods (intravenous infusions, esoteric laboratory measurements [inulin], and/or radioactive compounds [¹²⁵ I-iothalamate]). But a more practical way of determining the GFR has been the creatinine clearance, which requires a 24-hour urine collection, measurement of urine and serum creatinine, and use of the formula above.

In the absence of an indwelling catheter, the urine collection involves discarding the first morning urine and then collecting all urine for about the next 24 hours, up to and including the first morning urine the following day. All 24-hour urine collections should be assessed for accuracy and completeness by calculating the 24-hour total creatinine excretion; typical values are listed in the Reference Range section. If the patient includes 2 morning urines (overcollects) or misses one or more urine specimens (undercollects), this leads to an inaccurate GFR, which happens all too frequently.

In addition to reduced GFR, the other major form of CKD is proteinuria. Proteinuria is defined as more than 30 mg albumin per gram of creatinine in a random urine sample (24-hour collections are no longer needed or even suggested). ^[4] The reason that the urine albumin (or urine protein) concentration (mg/dL) cannot be used to assess the degree of proteinuria is that different individuals excrete different amounts of water depending on their fluid intake.

Historically, one addressed this limitation by collecting a 24-hour urine sample, allowing one to assess the 24-hour albumin (or protein) excretion. However, in any given spot urine sample, since the amount of water diluting the albumin (or protein) is the same as the amount of water diluting the creatinine, the ratio provides an accurate assessment of the degree of albuminuria (or proteinuria). Then, by applying the patient’s expected 24-hour creatinine excretion (related to muscle mass), one can estimate the 24-hour albumin (or protein) excretion. ^[12]

A study by Choi et al indicated that in kidney transplant patients with a functioning graft, those with a low creatinine-cystatin C ratio have a greater risk of death. The lowest tertile for the ratio had cutoffs of 0.86 and 0.73, in males and females, respectively. The 5-year survival rate was significantly lower in this tertile, the adjusted hazard ratio in this group for death with a functioning graft being 2.574. Sixty-two percent of the deaths in this tertile resulted from infection. (In the middle and highest tertiles together, the most common cause of death [39.3%] was cardiovascular disease.) ^[13]

Considerations

In 2006, a landmark study illustrated that one could calculate a reasonably good estimate of the GFR by using the serum creatinine, age, gender, and ethnicity of the patient. ^[14] This equation was named the MDRD equation because it was based on a study called the Modification of Diet in Renal Disease. A recommendation was made and largely adopted that laboratories report an estimated GFR (eGFR) with every measured serum creatinine study. Although the eGFR has a few limitations, it works quite well, especially in detecting reduced GFR at early stages. eGFR has been promoted as a valuable tool in screening for CKD. ^{[4, 11]}

One of its limitations is that the eGFR calculation is not valid in various situations (eg, pediatric patients, very elderly patients, pregnant individuals, extremes of body habitus, malnutrition, paraplegia, patients with skeletal muscle disease, those with rapidly changing kidney function).

Despite the MDRD equation being used by most clinical laboratories for reporting eGFR in adults, several other equations for calculating GFR can be used, some of which should be mentioned here (eg, the Chronic Kidney Disease Epidemiology Collaboration [CKD EPI], Bedside Schwartz, and co*ckcroft-Gault equations).

The MDRD equation was designed to detect reduced GFR, but it does not work well for values above 60 mL/min/1.73 m², which is why labs typically report such values simply as ">60." Using the same set of variables as the MDRD equation, the CKD EPI formula claims a higher level of accuracy with higher (normal) GFRs. ^[15]

The National Kidney Disease Education Program (NKDEP) recommendation is that eGFRs should be reported automatically for adults. When an estimation of GFR is needed for pediatric patients, the MDRD equation should not be used. Instead, the Bedside Schwartz equation, based on the patient's height and serum creatinine, is preferable. ^[4]

Last, although still in wide use, the co*ckcroft-Gault equation has been deservedly superseded by the newer equations already mentioned, except for, notably, drug dosing. Because most drugs received FDA approval prior to the existence of the MDRD equation, their renal dosing guidelines are typically based on the co*ckcroft-Gault equation. Although controversial, usually the differences in GFR generated by the two equations are insignificant. ^[16] When present, differences can often be ascribed to the fact that the assumptions underlying the co*ckcroft-Gault equation have not been met, as follows:

• Current creatinine methods are calibrated differently

• Failure to use the patient’s "lean body mass"

In assessing drug dosages needed in patients with coronavirus disease 2019 (COVID-19), a study by Larsson et al indicated that the co*ckcroft-Gault equation should not be utilized with modern creatinine analysis methods due to a worse performance in cases of COVID-19 than the MDRD1999, MDRD2006, CKD‐EPI, and revised Lund-Malmö equations, with the co*ckcroft-Gault equation providing the highest median eGFR. The study also reported that higher eGFRs are found with creatinine-based equations than with cystatin C–based equations in patients with COVID-19. ^[17]