Several studies have demonstrated that cystatin C concentrations, or GFR estimates based on cystatin C, predict mortality and cardiovascular disease better than GFR estimates based on serum creatinine.(4
) In this community-based cohort study, we found that two filtration markers which have not been compared prospectively, B2M, and to a lesser extent, BTP, share the advantage of cystatin C over creatinine-based estimates of GFR in predicting these outcomes. We further found that cystatin C, B2M and BTP also predict kidney failure more strongly than does serum creatinine-based eGFR. These data provide the first evidence that the advantages of cystatin C over serum creatinine in risk prediction are shared by other novel filtration markers, and show that several filtration markers together improve risk prediction beyond serum creatinine for a number of clinical outcomes. These improvements in prediction associated with cystatin C, BTP and B2M are beyond that provided by other relevant predictors of outcomes, including urinary ACR.
Serum creatinine provides useful estimates of GFR which are strong risk factors for a wide range of outcomes.(27
) However, it is unclear to what extent associations with creatinine under-estimate the full importance of decreased GFR. Creatinine production varies with muscle mass and catabolism and tubular secretion add to its renal elimination beyond filtration.(9
) As a result, it provides a useful but imprecise estimate of GFR whose errors are negatively correlated with muscle mass. This is especially true at near-normal levels of GFR. Low molecular weight proteins, including cystatin C, BTP and B2M, provide independent measures of kidney function which are less likely to be confounded by muscle mass.(12
) Each is produced at a relatively constant rate, is freely filtered by the glomeruli and is nearly completely reabsorbed and metabolized by the proximal tubules. Non-filtration influences on these markers may exist but are unlikely to be dominated by the same pathways as for serum creatinine. It is unknown whether the non-filtration factors found in some studies to be associated with circulating levels of cystatin C, including smoking, obesity, and inflammation, also affect BTP and B2M. The stronger associations with outcomes remained after adjustment for these factors, however.
Beta-trace protein acts as a prostaglandin D synthase, promoting the conversion of prostaglandin H2
to prostaglandin D2
) The major site of the brain form measured here is in the epithelial cells of the choroid plexus in the central nervous system.(16
) Several studies have found that serum levels of BTP are higher at lower levels of kidney function, and that BTP is comparable to creatinine for estimation of GFR.(14
) In a study of 146 patients, serum BTP-based eGFR equations had lower bias and greater precision in children (n=54) and adults (n=92) than did eGFR based on serum creatinine.(29
) Evidence of risk associated with elevated BTP is very limited. In a recent study of 227 patients with CKD (median GFR = 63 L/min/1.73 m2
; inter-quartile range = 38-96 mL/min/1.73 m2
), higher concentrations of BTP were strongly associated with incident ESRD or doubling of serum creatinine (median follow-up of 53 months), as were higher creatinine and cystatin C concentrations.(18
) It is uncertain what non-filtration factors may influence BTP.
Beta 2-microglobulin is a small subunit of the major histocompatibility (MHC) class I molecule present on all nucleated cells.(15
) B2M concentrations are increased in lymphoproliferative disorders and myeloma. Most studies analyzing the relationship between B2M concentration and GFR report relatively strong correlations, including one study of 44 participants with varying etiologies of kidney disease, in which the reciprocal of B2M was more strongly correlated with GFR by inulin than was serum creatinine.(15
) B2M is a predictor of survival in patients with lymphoproliferative disorders,(31
) and the association between higher B2M concentrations and mortality is well known for patients on maintenance dialysis.(32
) Few studies have examined the association between serum B2M concentrations and morbidity and mortality in the general population. The Tokyo Metropolitan Institute of Gerontology Longitudinal Interdisciplinary Study on Aging followed 1,034 individuals age 65 years and older for 8 years.(17
) The middle tertile and upper tertile of B2M concentrations were associated with significantly higher risk of mortality (HR = 2.02 [95%CI: 1.35-3.04] and 2.84 [95% CI, 1.92-4.20], respectively) than the lowest tertile.
This study shows that while serum creatinine-based filtration estimates are associated with increased risk, this risk is lower than that observed for any of the other three markers examined. All three novel markers were strongly associated with outcomes among participants with a baseline eGFRCKD-Epi ≥ 60 mL/min/1.73 m2, where associations with eGFRCKD-Epi are much flatter and sometimes inverse, as well as among patients with eGFRCKD-Epi 45-59 mL/min/1.73 m2 and no albuminuria, where markers distinguishing lower from higher risk are particularly needed. These two novel filtration markers, in addition to cystatin C, show promise in distinguishing risk in the range of kidney function where serum creatinine-based GFR estimates have a weaker relationship to risk. The reason for this difference could be that only serum creatinine suffers from strong negative confounding by lower muscle mass. The other markers could be more tightly correlated with GFR. Alternatively, they may be associated with other factors that both increase the concentration of these factors and increase the risk of mortality. The findings were similar for each of the outcomes studied, however, reducing the likelihood that a common third factor can explain these patterns.
The limitations of the study include no direct measure of GFR and a single baseline measurement of each marker. The observed associations should be replicated in similar populations and extended to more diverse settings, assays should be standardized, and the optimal set or markers for specific settings should be determined before making specific recommendations for use in clinical practice. The finding that cystatin C shares its predictive advantage over creatinine-based GFR estimates with two other novel filtration markers supports its use and interpretation in risk prediction and indicates the potential for improved risk prediction from using markers beyond creatinine. Defining the optimal combination of markers, however, will require further study across a range of settings and populations.
In summary, we found that B2M shares the advantages of cystatin C over serum creatinine in terms of predicting outcomes mortality, CHD, heart failure, and ESRD in the general population. Serum concentrations of BTP also predicted these outcomes more strongly than did estimated creatinine-based eGFR, but not as strongly as cystatin C and B2M. These markers strongly predicted events among individuals with normal creatinine-based eGFR, extending the range over which risk is related to markers of kidney function. Overall, multiple markers of kidney function improve risk prediction beyond serum creatinine alone, suggesting that they have promise as adjuncts to serum creatinine in evaluating kidney function and assessing prognosis in the general population.