A blood protein called cystatin C was a much stronger predictor of cardiovascular events and death in elderly people than the commonly used kidney marker creatinine.
2.27× cardiovascular death riskElderly adults with the highest cystatin C levels had more than double the risk of dying from cardiovascular causes compared to those with the lowest levels
What the researchers found
Cystatin C, a small protein produced by all nucleated cells and filtered by the kidneys, proved to be a far stronger predictor of death and cardiovascular events in elderly people than the traditional kidney marker creatinine.
Among 4,637 elderly community-dwelling participants followed for up to 9 years, higher cystatin C levels showed a clear dose-response relationship with all-cause mortality. Those in the highest cystatin C category (quintile 5c) had a 2.58-fold increased risk of death compared to the lowest quintile. The highest cystatin C concentration (≥1.29 mg/L) was independently associated with a 2.27-fold increased risk of cardiovascular death, a 1.48-fold increased risk of heart attack, and a 1.47-fold increased risk of stroke after adjusting for multiple variables. In contrast, the highest creatinine quintile was not independently associated with any of these three outcomes.
Why it matters
This landmark New England Journal of Medicine study helped establish cystatin C as a superior biomarker for kidney function and cardiovascular risk in older adults. Because creatinine levels are heavily influenced by muscle mass — which declines with age — creatinine can underestimate kidney impairment in elderly people. Cystatin C, being independent of age, sex, and muscle mass, provides a more accurate picture of kidney health and its downstream cardiovascular consequences.
The numbers in context
n=4,637 · up to 9 years follow-up · HR 2.58 for all-cause death (highest vs lowest cystatin C) · HR 2.27 for cardiovascular death · HR 1.48 for MI · HR 1.47 for stroke
How the study worked
This was a prospective cohort study using data from the Cardiovascular Health Study. Researchers measured both creatinine and cystatin C levels in blood samples from 4,637 elderly community-dwelling participants collected in 1992-1993. They divided participants into quintiles based on each biomarker level and followed them until June 2001, tracking deaths and cardiovascular events. Statistical models adjusted for multiple risk factors to isolate each biomarker's independent predictive value.
Who was studied
Community-dwelling elderly participants from the Cardiovascular Health Study cohort
What this study cannot tell us
The study population was community-dwelling elderly persons, so results may not generalize to younger adults or those in institutional care. The single baseline measurement of cystatin C and creatinine may not capture changes in kidney function over time. The abstract does not report the abstract's mention of the creatinine J-shaped curve's full details, suggesting low creatinine (possibly reflecting low muscle mass and frailty) also carried risk. Observational design means the association cannot prove causation.
How to read the evidence
This is a large prospective cohort study published in the New England Journal of Medicine — one of the most prestigious medical journals. With 4,637 participants and up to 9 years of follow-up, it provides strong observational evidence. The dose-response relationship strengthens the finding, though as an observational study it cannot prove causation.
When this study was published
Published in 2005, this study is over 20 years old but remains a foundational reference. Cystatin C has since been validated in numerous subsequent studies and incorporated into updated clinical guidelines for estimating kidney function.
The bigger picture
This study was instrumental in the medical community's growing adoption of cystatin C as a kidney function biomarker, especially for older patients. It helped shift clinical thinking about how kidney health connects to heart disease risk and demonstrated that traditional creatinine-based assessments can miss significant kidney impairment in the elderly. Today, cystatin C is increasingly used alongside creatinine in updated kidney function equations recommended by major nephrology guidelines.
Questions still open
- Could routine cystatin C screening in elderly patients lead to earlier interventions that reduce cardiovascular deaths?
- Does treating the underlying kidney dysfunction identified by cystatin C actually lower cardiovascular risk, or is cystatin C simply a marker of overall vascular damage?
- How do cystatin C levels perform as a risk predictor in younger or more diverse populations?
Common questions
What is cystatin C and why is it better than creatinine for kidney testing?
Does a high cystatin C level mean you will have a heart attack?
Read the original research
Cystatin C and the risk of death and cardiovascular events among elderly persons.
The New England journal of medicine, 352(20), 2049-60
Citation
Shlipak, Michael G; Sarnak, Mark J; Katz, Ronit; Fried, Linda F; Seliger, Stephen L; Newman, Anne B; Siscovick, David S; Stehman-Breen, Catherine. (2005). Cystatin C and the risk of death and cardiovascular events among elderly persons.. The New England journal of medicine, 352(20), 2049-60.