The serum creatinine concentration is widely interpreted as a measure of the glomerular filtration rate (GFR) and is used as an index of renal function in clinical practice. Glomerular filtration of creatinine, however, is only one of the variables that determines its concentration in serum. Alterations in renal handling and metabolism of creatinine and methodological interferences in its measurement may have a profound impact on the serum concentration of creatinine. We review the fundamental principles of physiology, metabolism, and analytical chemistry that are necessary to correctly interpret the serum creatinine concentration. These principles are then applied to important clinical circumstances, including aging, pregnancy, diabetes mellitus, drug administration, and acute and chronic renal failure. Despite numerous limitations, serum creatinine remains a useful clinical tool, but more accurate measures of renal function are frequently necessary.

Serum creatinine as an index of renal function: new insights into old concepts.

Background: Reliable serum creatinine measurements in glomerular filtration rate (GFR) estimation are critical to ongoing global public health efforts to increase the diagnosis and treatment of chronic kidney disease (CKD). We present an overview of the commonly used methods for the determination of serum creatinine, method limitations, and method performance in conjunction with the development of analytical performance criteria. Available resources for standardization of serum creatinine measurement are discussed, and recommendations for measurement improvement are given.

Methods: The National Kidney Disease Education Program (NKDEP) Laboratory Working Group reviewed problems related to serum creatinine measurement for estimating GFR and prepared recommendations to standardize and improve creatinine measurement.

Results: The NKDEP Laboratory Working Group, in collaboration with international professional organizations, has developed a plan that enables standardization and improved accuracy (trueness) of serum creatinine measurements in clinical laboratories worldwide that includes the use of the estimating equation for GFR based on serum creatinine concentration that was developed from the Modification of Diet in Renal Disease (MDRD) study.

Conclusions: The current variability in serum creatinine measurements renders all estimating equations for GFR, including the MDRD Study equation, less accurate in the normal and slightly increased range of serum creatinine concentrations [<133 μmol/L (1.5 mg/dL)], which is the relevant range for detecting CKD [<60 mL · min−1 · (1.73 m2)−1]. Many automated routine methods for serum creatinine measurement meet or exceed the required precision; therefore, reduction of analytical bias in creatinine assays is needed. Standardization of calibration does not correct for analytical interferences (nonspecificity bias). The bias and nonspecificity problems associated with some of the routine methods must be addressed.

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Recommendations for Improving Serum Creatinine Measurement: A Report from the Laboratory Working Group of the National Kidney Disease Education Program

Purpose: To review information on performance characteristics for tests that are commonly used to identify acute and chronic hepatic injury.

Data Sources and Study Selection: A MEDLINE search was performed for key words related to hepatic tests, including quality specifications, aminotransferases, alkaline phosphatase, γ-glutamyltransferase, bilirubin, albumin, ammonia, and viral markers. Abstracts were reviewed, and articles discussing performance of laboratory tests were selected for review. Additional articles were selected from the references.

Guideline Preparation and Review: Drafts of the guidelines were posted on the Internet, presented at the AACC Annual Meeting in 1999, and reviewed by experts. Areas requiring further amplification or literature review were identified for further analysis. Specific recommendations were made based on analysis of published data and evaluated for strength of evidence and clinical impact. The drafts were also reviewed by the Practice Guidelines Committee of the American Association for the Study of Liver Diseases and approved by the committee and the Association’s Council.

Recommendations: Although many specific recommendations are made in the guidelines, some summary recommendations are discussed here. Alanine aminotransferase is the most important test for recognition of acute and chronic hepatic injury. Performance goals should aim for total error of <10% at the upper reference limit to meet clinical needs in monitoring patients with chronic hepatic injury. Laboratories should have age-adjusted reference limits for enzymes in children, and gender-adjusted reference limits for aminotransferases, γ-glutamyltransferase, and total bilirubin in adults. The international normalized ratio should not be the sole method for reporting results of prothrombin time in liver disease; additional research is needed to determine the reporting mechanism that best correlates with functional impairment. Harmonization is needed for alanine aminotransferase activity, and improved standardization for hepatitis C viral RNA measurements.

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Diagnosis and Monitoring of Hepatic Injury. I. Performance Characteristics of Laboratory Tests

Prolonged reflux esophagitis leads to replacement of the esophageal squamous epithelium by columnar epithelium in some patients. This columnar epithelium resembles gastric or intestinal mucosa and has been implicated as a precursor of esophageal adenocarcinoma. A review of 14 cases of primary esophageal adenocarcinoma disclosed that 12 (86%) arose in a columnar epithelium-lined (Barrett’s) esophagus. Ten of the 12 patients had a hiatal hernia or symptoms of reflux esophagitis or both. In ten patients the columnar epithelium adjacent to and remote from the invasive adenocarcinoma showed a spectrum of abnormalities ranging from mild dysplasia to carcinoma in situ . These data support the concept that esophageal adenocarcinoma is one complication of a columnar epithelium-lined esophagus, and suggest that the invasive carcinoma evolves through a sequence of epithelial dysplasia and carcinoma in situ in most cases. Esophageal biopsy and cytology can detect this dysplasia, and should provide an effective means for monitoring patients with Barrett’s esophagus for impending malignancy.

Adenocarcinoma Complicating Columnar Epithelium-lined (Barrett’s) Esophagus

Six patients in whom "essential hypertension" led to nephrosclerosis and kidney failure received kidney transplants from normotensive donors. After an average follow-up of 4.5 years, all were normotensive and had evidence of reversal of hypertensive damage to the heart and retinal vessels. These six patients, all of whom were black, and six control subjects matched for age, sex, and race were admitted to the General Clinical Research Center for 11 days for observation of their blood pressure and their responses to salt deprivation and salt loading. Mean arterial pressure (+/- S.E.M.) among the patients who had previously had essential hypertension was similar to that of the normal controls (92 +/- 1.9 vs. 94 +/- 3.9; P not significant), and both groups had similar responses to salt deprivation and salt loading. Thus, essential hypertension in human beings is shown to be similar to the hypertension seen in spontaneously hypertensive rats in that both can be corrected by transplantation of a kidney from a normotensive donor. This observation supports the concept of the primary of the kidney in causing essential hypertension.

Remission of Essential Hypertension after Renal Transplantation

We have evaluated a commercially available, direct, solid-phase radioimmunoassay kit for progesterone determination in serum or plasma. The assay is precise, within-run precision (CV) in the clinically significant ranges being 2.5 to 5.2%, between-run 5.5 to 5.8%. Mean analytical recovery of different concentrations of progesterone added to serum was 99.7% (range 95.3 to 102.7%). Fourteen closely related steroids showed no cross reactivity. The minimum detection limit was 0.5 microgram/L. Luteal-phase progesterone concentrations in serum were increased (greater than 3 micrograms/L) in 19 normal ovulatory menstrual cycles and decreased (less than 1.5 micrograms/L) in two nonovulatory cycles. We found this direct assay for progesterone to be analytically and clinically sound, and useful for assessing luteal-phase function.

Evaluation of a direct solid-phase radioimmunoassay for progesterone, useful for monitoring luteal function

Evaluation of a new commercial radioassay kit for aldosterone using an iodinated tracer.

An atomic absorption method is described for determining lead in blood by means of the carbon rod atomizer. With the procedure, only a dilution of the whole blood sample is required, and results are comparable to those obtained by the more generally used atomic absorption flame technique. Advantages of the carbon rod include rapid analysis, simple sample preparation, and small sample volumes.

Carbon rod atomizer applied to measurement of lead in whole blood by atomic absorption spectrophotometry.

Pepsin secretion, pepsinogen, and gastrin in "Barrett's esophagus." Clinical and morphological characteristics.

We determined appropriate temperatures for sample storage and the resulting stability of 14 analytes commonly radioimmunoassayed in the clinical laboratory. Serum specimens to be tested for concentrations of cholylglycine, cortisol, digoxin, ferritin, follitropin, immunoglobulin E, lutropin, prolactin, thyroxin (also blood-spot thyroxin), triiodothyronine, and triiodothyronine uptake could be stored for up to two weeks at room temperature, refrigerated, or frozen without any loss of analyte activity. Specimens for insulin testing require freezing or refrigeration, and specimens for gastrin testing should be stored at -70 degrees C for optimal results.

Norman P. Kubasik

Papers

Evaluation of a direct solid-phase radioimmunoassay for progesterone, useful for monitoring luteal function

Evaluation of a new commercial radioassay kit for aldosterone using an iodinated tracer.

Carbon rod atomizer applied to measurement of lead in whole blood by atomic absorption spectrophotometry.

Pepsin secretion, pepsinogen, and gastrin in "Barrett's esophagus." Clinical and morphological characteristics.

Effect of duration and temperature of storage on serum analyte stability: examination of 14 selected radioimmunoassay procedures.