In this meta-analysis of 16 studies, investigators evaluated the use of cystatin C, alone or with creatinine, to calculate the estimated glomerular filtration rate (eGFR). Measurement of cystatin C improved the prediction of outcomes in chronic kidney disease.
The eGFR is the clinical standard for the assessment of kidney function. The eGFR thresholds for the definition and staging of chronic kidney disease are based on risk, but the use of creatinine to determine the eGFR has limitations in risk prediction, particularly in patients with reduced muscle mass.
• What are the determinants of serum creatinine besides glomerular filtration, and how might these confound the association between creatinine-based eGFR and outcomes?
It is well known that the non-GFR determinants of serum creatinine, including muscle mass, diet, and physical activity, can confound the associations between the creatinine-based eGFR and outcomes. The authors observed that the creatinine-based eGFR had the weakest association with death from any cause among the three GFR estimates (the other two being a combination of creatinine and cystatin C and cystatin C alone) and had a marked reverse J-shaped association. The hypothesized mechanism is that serum creatinine levels are lower than expected for the level of GFR in patients who are in poor health and who are most likely to die. Non-GFR determinants of cystatin C also exist, though they are quantifiably smaller than those of creatinine.
• What were the results of this study with respect to the use of cystatin C and the role of eGFR in risk categorization?
The authors indicate that this study provides evidence that the measurement of cystatin C improves the role of eGFR in risk categorization, as judged by the risk of death from any cause and, to a lesser extent, by the risks of death from cardiovascular causes and end-stage renal disease. Most notably, reduced values for cystatin C-based eGFR and eGFR based on combined measurements of creatinine and cystatin C had a consistent linear association with increased risks of death from any cause and from cardiovascular causes for all eGFR levels below approximately 85 ml per minute per 1.73 m2, which is well above the threshold of 60 ml per minute per 1.73 m2 for the detection of chronic kidney with a creatinine-based calculation of the eGFR.
Morning Report Questions
Q: How does the calculation of the eGFR with a combination of creatinine and cystatin C compare to the use of cystatin C alone?
A: Recent studies have shown that calculation of the eGFR with a combination of creatinine and cystatin C more accurately reflects measured GFR than either marker alone, findings that are probably due to the lesser overall effects of non-GFR determinants of either marker when both markers are included. However, the authors found that eGFR calculated with the use of both markers had a weaker association with the risk of death from any cause than did the cystatin C-based eGFR. Because analyses of prognosis are most heavily influenced by the events (in this case, deaths), the confounding by non-GFR determinants of creatinine in persons who are most susceptible to illness may weaken the association between eGFR based on combined measurements and longitudinal outcomes more than with cross-sectional comparisons with measured GFR. Thus, calculation of the eGFR with the use of combined measurements may provide the most accurate eGFR overall but not in some subgroups of patients in whom creatinine levels are reduced and risk is high. Alternatively, if non-GFR determinants of cystatin C augment its association with the risk of death, then they will have a greater effect on the cystatin C-based eGFR than on the eGFR that is based on combined measurements.
Q: What are recommendations in patients who are currently considered to have chronic kidney disease on the basis of an eGFR less than 60 ml per minute per 1.73 m2 without markers of kidney damage?
A: Recent guidelines suggest the use of cystatin C to validate the diagnosis of chronic kidney disease in patients who are currently considered to have chronic kidney disease solely on the basis of a creatinine-based eGFR of less than 60 ml per minute per 1.73 m2, without albuminuria or other markers of kidney damage. In this study, 42% of participants with a creatinine-based eGFR of 45 to 59 ml per minute per 1.73 m2 had a cystatin C-based eGFR of 60 ml per minute per 1.73 m2 or more, and those participants had a 34% reduction in the risk of death and an 80% reduction in the risk of end-stage renal disease, as compared with participants for whom the eGFR was not reclassified.