Identification of individuals with chronic kidney disease who are most likely to progress to ESRD or mortality is central in the clinical management of CKD. Such identification, however, is hampered by the shortcomings of current methods to assess kidney function by serum creatinine.23, 24
This has led to the search for other biomarkers of kidney function. Long-term follow-up of a cohort of African Americans with hypertensive chronic kidney disease afforded us the opportunity to compare the usefulness of mGFR, serum creatinine, eGFRSCr
, cystatin C, and BTP to predict ESRD and mortality.
Higher concentrations of each marker were significantly associated with higher risk of incident ESRD, but BTP predicted ESRD more strongly than did the other markers, including mGFR. Each of the other markers remained significantly associated with ESRD after adjustment for baseline mGFR, but BTP was again more strongly associated with ESRD than were the other markers. The addition of any marker to a model with covariates and mGFR significantly improved risk classification of study participants. Higher concentrations of each marker were also significantly associated with ESRD or mortality, but these associations were weaker than for ESRD alone. Again, BTP was more strongly associated with this outcome than were the other markers, remaining significant after adjustment for mGFR and relevant covariates.
Synthesis of beta-trace protein occurs predominately in the central nervous system and it is one of the main components of cerebrospinal fluid.25
It may be a useful marker of kidney function because of its low molecular weight (23-29 kDa) and its lack of affinity for protein binding.25, 26
It acts as a prostaglandin D synthase, promoting conversion of prostaglandin H2 to prostaglandin D2.8
Previous studies on BTP and kidney function have reported that an eGFR equation based on serum BTP had lower bias and greater precision than eGFR based on serum creatinine. 27
It is uncertain, however, what non-filtration factors affect circulating levels of BTP.
A recent study of 227 European men and women with nondiabetic CKD and reduced kidney function at baseline explored the ability of serum creatinine, cystatin C, and BTP to predict CKD progression, defined as doubling of baseline creatinine and/or ESRD.28
The concentrations of all three markers were significantly associated with GFR cross-sectionally. All three markers also were similarly predictive of CKD progression. Our results are in general agreement with these findings, though in our study BTP predicted ESRD more strongly than did cystatin C, serum creatinine, or eGFRSCr
. The results for serum creatinine as a predictor of outcomes in the previous study may be biased by using a change in serum creatinine as one component of the outcome definition. Other studies have reported that serum creatinine is less sensitive to small changes in kidney function compared to cystatin C and BTP.6, 29, 30
The range of GFR levels among the AASK population (i.e., 20-65 mL/min/1.73 m2
), however, is generally within the range in which serum creatinine is a relatively accurate estimate of GFR.
Cystatin C has been proposed as a better marker of kidney function than serum creatinine, in part because it is less sensitive to differences in muscle mass.31, 32
Cystatin C is a stronger predictor of cardiovascular events, cardiovascular mortality, and all-cause mortality than is serum creatinine or eGFR based on serum creatinine.33, 34
Among 825 participants with stage 3 or 4 non-diabetic CKD in the Modification of Diet in Renal Disease (MDRD) Study, 1/cystatin C had a stronger association with all-cause mortality and CVD mortality than did 1/creatinine.31
The associations of 1/creatinine with kidney failure, however, was slightly stronger than that for 1/cystatin C (relative risk per 1 standard deviation of 2.81 for 1/creatinine and 2.36 for 1/cystatin C). Similarly, in our study, the association between cystatin C and ESRD was generally similar to the association between serum creatinine and ESRD, but cystatin C was more strongly associated with the combined outcome of ESRD or death than was serum creatinine or eGFRSCr
A limited number of previous studies have found serum creatinine, cystatin C, and beta trace protein to better predict kidney outcomes than mGFR. 28, 31
In our study, beta trace protein and cystatin C predicted ESRD more strongly than did mGFR. Each of the endogenous markers also predicted ESRD after adjustment for mGFR. This may be related to imprecision in mGFR measurement, including hourly and daily variations and deviations from measurement protocol. 35
Previous studies have shown that between-day coefficients of variation (CV) can vary between 6.3-16.6% when using I-iothalamate clearance.36, 37
We were not able to explicitly test this hypothesis. Alternatively, these markers may represent non-GFR factors that are related to progression to ESRD. It is important to note that the inclusion criteria for the AASK study required participants to have an mGFR between 20 and 65 mL/min per 1.73 m2
. This restricted range of mGFR values may limit the maximum statistical association between mGFR and outcomes. No such restriction was placed on the other markers, allowing them to have their full statistical association with outcomes. This may explain, in part, the residual association between these markers and outcomes after adjustment for mGFR.
In our study, ESRD was defined by kidney transplant or initiation of dialysis. As the decision to implement either treatment is likely to be influenced by the physicians’ interpretation of the measured mGFR, serum creatinine, and eGFR, we could expect that the association between these markers and ESRD would be biased upwards. Despite this bias, higher BTP was more strongly associated with ESRD than these markers, even after adjustment for mGFR.
Each of the endogenous markers was reasonably well-correlated with mGFR. Serum creatinine had a weaker correlation with mGFR than did cystatin C or BTP. However, estimated GFR based on serum creatinine, age, and sex had the strongest correlation with mGFR. This may be due to the strong dependency of creatinine on muscle mass, for which age and sex act as proxies in the GFR-estimating equations. The correlation of eGFRSCr
with mGFR may be higher than in other studies, as the estimating equation used was developed in a pilot study for the AASK trial.16
The results of our analysis are promising but are limited by use of a select population. The AASK study enrolled African Americans with hypertensive kidney disease with no other identifiable cause of kidney disease. Further work needs to be done in a more generalizable population. The ability of these markers to predict mortality, cardiovascular disease, and other outcomes remains to be better studied. The use of the AASK study has distinctive advantages, as well. The study includes a high-risk group with well-controlled blood pressure. Baseline characteristics, including mGFR and proteinuria, were systematically collected and outcomes were carefully and thoroughly ascertained over a long follow-up period.
In summary, we found that BTP predicts ESRD more strongly than other markers of kidney function evaluated, including cystatin C, serum creatinine, eGFRSCr and mGFR. The results of this study suggest that, although these endogenous markers have relatively similar correlations with mGFR, the markers may be differentially associated with progression to ESRD, and that BTP and cystatin C may be useful adjuncts to serum creatinine or mGFR in evaluating risk for progression of kidney disease. Further work needs to be done to determine the best way to combine information from various markers to evaluate risk for specific adverse outcomes.