Proteins of MW not exceeding 40–50 kDa, often called microglobulins, are freely filtered by the glomerulus and then almost completely reabsorbed (up to 97–99%) by the proximal convoluted tubule. Although they are reabsorbed by the tubule, these proteins do not return to the circulation because within the tubule itself they are degraded into lysosomes, where specific proteolytic enzymes break down the polypeptide chains into single amino acids. Consequently, if the catabolism of a protein of low MW is renal, its plasma concentration can be directly correlated to the amount of renal filtrate because the lower the GFR, the more it increases in the circulation. Another consequence is that the determination of the clearance of a microglobulin has no clinical or pathophysiological significance. Unfortunately, it has not been easy to identify a protein of low MW that in some way could be proposed as a biochemical marker of GFR because it should be eliminated exclusively renally and its concentration should not be influenced by extrarenal factors. Moreover, this protein should be able to be measured in the laboratory by simple, cheap, and reliable methods, easily optimizable in the clinical routine. For these reasons, some proteins, such as β2-microglobulin, lysozyme, and α1-microglobulin, have not been used as possible plasma biomarkers of GFR, whereas other proteins, such as cystatin C and, more recently, β-trace proteins, have been studied in detail.

Cystatin C

 Cystatin C, also called γ-trace protein or post-γ protein because of its electrophoretic mobility, is a basic protein of MW of 15,359 Da containing 120 amino acids. It belongs to the cystatin superfamily together with about a dozen other cysteine protease inhibitors. Cystatin C is expressed by most tissues and many cells, including skin fibroblasts and macro phages, neurons, embryonic tissues, smooth muscle cells, and neuroendocrine cells. The mature form consists of a single non-glycosylated polypeptide chain with two intramolecular disulfide bridges. The only posttranslational modification demonstrated to date is the 50% hydroxylation of proline at position 3. The monomeric form secreted by cells represents the active form of the protein. At physiological pH, cystatin C is a cationic protein and has an isoelectric point (IP) of 9.3. In humans, the cystatin C gene is located on chromosome 20p11.2 and belongs to the so-called class of housekeeping genes, i.e., “conservative” genes, constantly expressed in all the cells of the body. The kidney is the main catabolic sites of cystatin C. Due to its low MW, the protein is freely filtered by the glomerulus and almost completely reabsorbed and catabolized in the cells of the proximal con voluted tubule. Under physiological conditions, it is present in the urine only in trace amounts. The plasma concentration of cystatin C depends mainly on GFR because its extrarenal elimination rate is negligible and it is not affected by extrarenal factors, such as muscle mass, diet, binding to other plasma proteins, etc. Consequently, cystatin C increases in the circulation as the GFR decreases. Additionally, it does not cross the placental barrier and, therefore, the plasma con centration at birth and in the first week of life is not affected by maternal concentration, unlike creatinine. Since 1994, various immunological methods have been developed for the routine determination of cystatin C; in particular, nephelometric methods are limited to a few platforms, whereas turbidimetric methods can be optimized on many analytical platforms. More than 20 years after the release of the first routine method, cystatin C has entered the clinical evaluation of a patient affected by renal disease. Efforts have also been made to standardize methods for cystatin C: in 2010, the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) working group made available a primary calibrator standard (ERM-DA471/IFCC); the availability of an absolute method in liquid chromatography combined with mass spectrometry now allows certification of the exact content of the protein in biological fluids and calibration materials. Despite these advances, the reduction in variability among methods resulting from standardization has been described in only a few studies but not in others, confirming the presence of controversy over whether or not the analytical problems plaguing the determination of cystatin C are resolved. In the last 15 years, all of the most important clinical studies have shown that cystatin C has a high sensitivity and a high positive predictive value for renal disease. In other words, data from the literature confirm that cystatin C is an early index of even mild reduction in GFR. Moreover, cystatin C is a better prognostic index of death and cardiovascular events than creatinine. Cystatin C has been incorporated into equations for estimating filtrate alone or in combination with creatinine, proving to make GFR estimation more accurate, especially considering the standardization of analytical methods. In particular, the CKD-EPI equation, which includes both creatinine and cystatin C in the calculation, provides better performance than either the creatinine-only CKD-EPI or the cystatin C-only CKD-EPI, although not in all clinical conditions, such as in an organ transplant patient. It is desirable that the use of cystatin C becomes part of routine laboratory practice, especially in the evaluation of patients in whom filtrate reduction is mild but not without the risk of renal disease progression. Conversely, the determination of cystatin C in patients with GFR <30  mL/min/1.73 m² is inappropriate because at those filtrate levels creatinine is more than sufficient to assess dis ease progression and estimate GFR.

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مواضيع ذات صلة

NGAL

Biomarkers of Tubulo-Interstitial Injury

Immunofluorescence Assay (IFA)

Enzyme-Linked Fluorescent Assay (ELFA)

Diagnostic Evaluation of Lyme disease

red blood cell count (RBC count, Erythrocyte count)

rabies-neutralizing antibody test

prothrombin time (PT, Protime, International normalized ratio [INR])

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Creatinine test for Diagnosis of Kidney Diseases

Urea test for Diagnosis of Kidney Diseases

Standard Urine Test for Diagnosis of Kidney Diseases