ReviewAlpha 1-microglobulin: clinical laboratory aspects and applications
Introduction
The evaluation of renal tubular function is an important issue in clinical laboratory medicine. Detection of urinary microproteins can help to detect renal abnormalities at an early stage and differentiate the various forms of renal and urological pathology by less invasive techniques. For many years, beta 2-microglobulin has been a golden standard urinary marker protein. However, the diagnostic utility of this protein is hampered by its poor stability at acid pH. The stable microprotein alpha 1-microglobulin (A1M) offers an interesting alternative for evaluating tubular function.
Furthermore, A1M is an intriguing multifunctional immunomodulatory protein. Numerous studies have revealed a broad spectrum of clinical applications. This review aims at giving an overview of recent developments in the basic knowledge, analysis and clinical use of A1M. To accomplish this, we have performed a systematic review in Pubmed of the peer-reviewed literature until November 15, 2003.
Section snippets
Synthesis and genetics
A1M is encoded by a unique gene encoding both A1M and another protein, bikunin, which has no other known relation to A1M than the co-synthesis [1]. The gene is translated into the A1M-bikunin precursor, which is subsequently cleaved. Bikunin is the small, active subunit of protein/carbohydrate complexes that constitute the inter-alpha-inhibitor family [2].
The human AMBP gene has been cloned [3] and has been mapped to the 9q32–33 region [4]. The AMBP gene has a weak minimal promoter [5]. A
Methods
Various immunoassays for the measurement of A1M have been introduced. Early assays for A1M involved electroimmunoassay and single radial immunodiffusion [9], [14], [56], [57]. Later on, solid phase radioimmunoassay followed [58]. Automated immunoassays using polystyrene particles coated with antibodies (allowing “kinetic” assays) as well as enzyme immunoassays have been developed [59]. Analytical sensitivities as low as 0.8 mg/l were reported with a between-run imprecision (CV) of 11–16% [59].
Clinical aspects
Table 1 summarizes the most important conditions related to A1M and its concentration. The major clinical application remains the use of urinary A1M as a marker for proximal tubular damage. The other potential applications are less documented.
A1M levels are very stable in several pathological conditions: no significant changes were seen in serum of patients with neoplastic diseases, central nervous system disorders, infections, rheumatoid arthritis and other disorders [56], [58], [72]. With a
Reference values
Determination of A1M in human plasma or serum is complicated by the presence of different forms of the protein. Consequently, reports on normal A1M concentrations in human plasma/serum have varied widely especially since an international accepted standard is not available.
Table 3 summarizes some of the most important existing data for the most widely used biological fluids. Several investigators have measured free A1M and IgA-A1M separately in normal serum or plasma [60], [61], [62], [71], [109]
Post-analytical aspects
Results of measuring urinary marker proteins are still difficult to interpret. Using a parameter set including A1M, it was possible to separate various renal diseases by analysis of second morning urine. In order to compensate for variation due to urinary dilution, usually creatinine excretion is used [62], [110], [112], [113]. A1M was useful to separate primary glomerulopathies from tubulo-interstitial diseases. Application of these techniques can help to detect renal abnormalities at an
Conclusion
A1M is an immunosuppressive protein with an unknown exact biological function. Many unusual and intriguing properties of the protein have been revealed. The protein acts as a mediator of bacterial adhesion to polymer surfaces and might play a role in renal lithogenesis. In the clinical laboratory, sensitive immunoassays allow us to use A1M determination for clinical purposes. Although A1M is not an acute phase protein, changes in the plasma/serum concentrations have been observed in several
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