Decreased Fetuin-A Levels and Increased Burden of Cardiovascular Disease
Decreased Fetuin-A Levels and Increased Burden of Cardiovascular Disease
Hermans MM, Brandenburg V, Ketteler M, et al
Kidney Int. 2007;72:202-207
This is a prospective cohort study of 996 Dutch patients incident to hemodialysis and peritoneal dialysis in which the investigators measured serum fetuin-A and C-reactive protein and correlated both with patient survival. In this cohort, higher serum fetuin-A levels were associated with lower age, lower C-reactive protein levels, higher serum albumin, and higher calcium levels (all P<.01). Mortality risks (cardiovascular and all-cause) were higher among patients with the lowest serum fetuin-A levels in univariate analysis (both P<.001). Lower fetuin-A levels remained significantly associated with increased risk for mortality when controlled for multiple clinical and laboratory variables. Interestingly, the association between calcium, phosphorus, and mortality and between fetuin-A and mortality seem to confound each other to some extent in that the strength (but not the significance) of the risk between fetuin-A and mortality was somewhat reduced when calcium and phosphorus were added to the model.
Fetuin-A is a negative acute-phase protein and a powerful circulating calcification inhibitor of hydroxyapatite formation. The literature examining the associations between decreased fetuin-A levels and increased burden of cardiovascular disease as well as increased risk for poorer outcomes is beautifully summarized and discussed by Mehrotra in a commentary accompanying the article.
For the epidemiologist, this article adds one more piece to the puzzle of why end-stage renal disease (ESRD) patients have accelerated atherosclerosis. For the clinician, the message is even stronger although significantly more subtle.
In the care of patients with ESRD, clinicians are provided benchmarks that have been established through examination of associations between certain thresholds of these variables and mortality in large observational studies (eg, calcium ≤ 9.5 mg/dL, phosphorus ≤ 5.5 mg/dL, and Kt/V ≤ 1.2). While some benchmarks have been validated in clinical trials (eg, Kt/V), some have not (eg, calcium and phosphorus). If we operate under the assumption that measurement of the divalent cation calcium itself (chosen as an example for its relevance in this study) mechanistically confers all the risk that is described in the observational studies linking higher calcium levels to mortality, then it would follow that our actions should clearly be entirely directed toward lowering serum calcium levels. However, the significant and inverse association between serum fetuin-A and higher calcium levels and that the calcium and fetuin-A confound the relationship with mortality suggest that calcium in some part may be a marker of other processes (eg, those that result in lower serum fetuin-A levels) and that the mortality risk associated with higher calcium levels may not be diminished merely by lowering serum calcium.
Our patients have extraordinarily high morbidity and mortality. In our efforts to practice evidence-based medicine, we appropriately utilize the plethora of available observational data to its fullest. However, studies such as the one by Hermans and colleagues make it clear that we need to think outside of the box to truly be able to understand why cardiovascular disease processes are so aggressive in ESRD. Such studies need to make healthy skeptics out of all of us. The answers to our questions on how to lower mortality are probably not as simple as changing medications or lowering dialysate calcium.
Abstract
Hermans MM, Brandenburg V, Ketteler M, et al
Kidney Int. 2007;72:202-207
This is a prospective cohort study of 996 Dutch patients incident to hemodialysis and peritoneal dialysis in which the investigators measured serum fetuin-A and C-reactive protein and correlated both with patient survival. In this cohort, higher serum fetuin-A levels were associated with lower age, lower C-reactive protein levels, higher serum albumin, and higher calcium levels (all P<.01). Mortality risks (cardiovascular and all-cause) were higher among patients with the lowest serum fetuin-A levels in univariate analysis (both P<.001). Lower fetuin-A levels remained significantly associated with increased risk for mortality when controlled for multiple clinical and laboratory variables. Interestingly, the association between calcium, phosphorus, and mortality and between fetuin-A and mortality seem to confound each other to some extent in that the strength (but not the significance) of the risk between fetuin-A and mortality was somewhat reduced when calcium and phosphorus were added to the model.
Fetuin-A is a negative acute-phase protein and a powerful circulating calcification inhibitor of hydroxyapatite formation. The literature examining the associations between decreased fetuin-A levels and increased burden of cardiovascular disease as well as increased risk for poorer outcomes is beautifully summarized and discussed by Mehrotra in a commentary accompanying the article.
For the epidemiologist, this article adds one more piece to the puzzle of why end-stage renal disease (ESRD) patients have accelerated atherosclerosis. For the clinician, the message is even stronger although significantly more subtle.
In the care of patients with ESRD, clinicians are provided benchmarks that have been established through examination of associations between certain thresholds of these variables and mortality in large observational studies (eg, calcium ≤ 9.5 mg/dL, phosphorus ≤ 5.5 mg/dL, and Kt/V ≤ 1.2). While some benchmarks have been validated in clinical trials (eg, Kt/V), some have not (eg, calcium and phosphorus). If we operate under the assumption that measurement of the divalent cation calcium itself (chosen as an example for its relevance in this study) mechanistically confers all the risk that is described in the observational studies linking higher calcium levels to mortality, then it would follow that our actions should clearly be entirely directed toward lowering serum calcium levels. However, the significant and inverse association between serum fetuin-A and higher calcium levels and that the calcium and fetuin-A confound the relationship with mortality suggest that calcium in some part may be a marker of other processes (eg, those that result in lower serum fetuin-A levels) and that the mortality risk associated with higher calcium levels may not be diminished merely by lowering serum calcium.
Our patients have extraordinarily high morbidity and mortality. In our efforts to practice evidence-based medicine, we appropriately utilize the plethora of available observational data to its fullest. However, studies such as the one by Hermans and colleagues make it clear that we need to think outside of the box to truly be able to understand why cardiovascular disease processes are so aggressive in ESRD. Such studies need to make healthy skeptics out of all of us. The answers to our questions on how to lower mortality are probably not as simple as changing medications or lowering dialysate calcium.
Abstract