Reference intervals for the glomerular filtration rate and cell-proliferation markers: serum cystatin C and serum β₂-microglobulin/cystatin C-ratio

Abstract

Recent studies have indicated that serum and plasma cystatin C are better markers for glomerular filtration rate (GFR) than serum creatinine, ubiquitously used for this purpose. To fully exploit the value of serum and plasma cystatin C as GFR markers, reliable age and sex-correlated reference intervals are required. The present study comprised cystatin C determinations in plasma and sera from 259 individuals from a well-defined area in the southernmost part of Sweden. From demographic lists two men and two women were randomly selected from each one-year birth cohort above 20 years of age. No sex differences were found for plasma and serum cystatin C, whereas an increase in the cystatin C levels with age was noted, corresponding to the known age-related decrease in GFR. The following reference intervals are recommended for practical clinical use: S-Cystatin C (both sexes): 20-50 years, 0.70-1.21 mg l-1 and 50+ years, 0.84-1.55 mg l-1. The same samples were also used for determination of beta 2-microglobulin levels in order to calculate reference intervals for the beta 2-microglobulin/cystatin C-ratio, which is a more distinct marker for cell proliferation, particularly lymphoproliferation, than is the serum level of beta 2-microglobulin alone, since the ratio should be virtually uninfluenced by GFR. The beta 2-microglobulin/cystatin C-ratios were uninfluenced by sex and age and 1.45-2.43 is recommended as the serum reference interval for practical clinical use. Serum creatinine was determined in the same samples and the creatinine level was found to be strongly influenced by sex and weakly by age.

Comparison of Serum Concentrations of β-Trace Protein, β2-Microglobulin, Cystatin C, and Creatinine in the US Population

“…This is consistent with prior reports that demonstrated minimal effects of age on bTP (29,30) or b2M (29) in younger adults (aged ,22 years), but significant associations with age, particularly for b2M, in older adults (31)(32)(33). The positive associations of bTP and b2M with age were also seen with CysC and creatinine, which likely reflect a higher prevalence of decreased GFR with age (27).…”

“…Whereas some studies describe higher bTP concentrations in adult men compared with women (35), most studies have shown no sex differences in children (29,30). b2M has not been shown to differ by sex in youth (29), but some studies have reported higher b2M concentrations in adult men compared with women (33), whereas others report no sex differences (31,32). Our data suggest that men have higher concentrations of bTP than women aged ,30 years and .50 years, whereas serum concentrations of b2M were generally greater in men aged ,40 years.…”

Age, Gender, and Race Effects on Cystatin C Levels in US Adolescents

“…This contrasts to previous work that concluded that cystatin C levels were independent of age in pediatric populations (11,14). Several authors noted an age-related rise in cystatin C levels after the age of 50 to 60 yr (15,32,39), which presumably reflects a decline of kidney function. It is known that there are no changes in GFR during adolescent maturation (40); thus, in this population of generally healthy adolescents aged 12 to 19 yr, the age-related variation in cystatin C levels is likely related to variation in cystatin production.…”

Cystatin C: current position and future prospects

“…These results contradict the older studies which did not recommend establishing sex-related reference values (24,(33)(34)(35)(36)(37), except for results found by Pergande and Jung (38).…”

“…Caution is however required in very young children and premature infants in whom high CysC values may reflect low GFR as part of the renal maturation process (35,42). Most studies in adults show that age has a significant impact on CysC concentrations, implying different reference values for people over 50-60 years old (30,33,34,37). It is important to note that reference values in both adults and children are systematically lower when measured by the Dade-Behring Siemens PENIA method (vs. the various PETIA applications of the DakoCytomation kit) ( Table 2).…”