In this cohort of older adults, both ACR and impaired GFR, as measured by elevated serum cystatin C, were independently associated with increased risk of all-cause and cardiovascular mortality in older adults. Among persons without CKD (eGFR > 60 ml/min/1.73 m2), MA and pre-CKD identified different segments of the population and were associated with increased mortality risk; together, they were associated with more than 2-fold risk of death. In addition, we observed a linear gradient in mortality risk associated with albuminuria levels below the threshold considered for MA. A weaker association was observed between ACR and MI or CHF, particularly in those with normal kidney function. The risks associated with impaired GFR and ACR remained significant after adjustment for each other and numerous potential confounders including diabetes, hypertension and prevalent cardiovascular disease, and were not affected by race.
The reasons for the additive risks associated with the presence of albuminuria or impaired GFR are not entirely clear. The two measures are weakly correlated, and a significant proportion of those with impaired GFR does not have MA, and vice versa, as noted above [13
]. The pattern of independent mortality risk that we observed suggests that these two clinical markers may operate through different pathophysiologic mechanisms.
Albuminuria is indicative of damage to glomerular basement membranes and may be reflective of vascular and endothelial damage [33
]; it has been linked with inflammation and dysfunction of the coagulation system, possibly explaining its association with higher rates of cardiovascular events and cardiovascular mortality [34,35
]. Impaired glomerular filtration rate leads to decreased clearance of numerous potentially toxic endogenous and exogenous by-products, and is also associated with higher levels of systemic inflammation [25,36
]. Inflammation is noted with small changes in GFR, but other effects of impaired GFR have been noted primarily at more advanced degrees of kidney dysfunction. Our results persisted despite adjustment for measured comorbidities, but it is possible that preclinical kidney disease is also a marker for more severe or long-standing diseases such as hypertension, diabetes and dyslipidaemia.
Our study provides more detailed information about early kidney dysfunction in older adults, more complete assessment of outcomes and a more diverse cohort of older adults than those seen in previous studies of albuminuria and impaired eGFR. The recent studies using ACR and creatinine-based eGFR noted additive relationships between decreased eGFR and albuminuria, but did not use cystatin C, and either did not examine [14
] or found equivocal or minimally increased risk [6,15
] of mortality above an estimated eGFR of 60 or 75 ml/min/1.73 m2
. Although the populations under study had slightly different demographic characteristics, both include a substantial proportion of older adults and are, we believe, comparable. Our study, by contrast, showed increased risk of mortality in the subgroup with preclinical kidney disease independent of albuminuria.
Our results were similar for CHF, with graded increases in risk based on increasing levels of ACR and decreasing kidney function. This pattern was attenuated for MI, and MA and preclinical kidney disease had only a modest relationship with this outcome. This is likely due to different underlying mechanisms, but may also partially reflect a lack of statistical power due to smaller numbers of events.
We noted that those with both MA and CKD were at markedly increased risk of deleterious outcomes in our study, with a nearly 4-fold risk of all-cause mortality even after adjustment for other comorbidities. This group also had the highest rates of incident CHF and MI. This emphasizes the importance of assessing MA in older adults with CKD, and vice-versa, to improve risk estimation and to target interventions to this extremely high-risk group.
These findings support the concept that kidney disease should be defined using albuminuria and impaired GFR as separate markers, since they contribute separately to cardiovascular risk. Since these markers are elevated in different segments of the population, screening strategies should be tailored based on age and likelihood of having these abnormalities [13
Our results support the use of cystatin C as an independent risk marker in older adults. The subgroup in our study with preclinical kidney disease and no MA had a 50% increased risk of all-cause mortality in follow-up. This group had an average MDRD eGFR of 80 ml/min/1.73 m2, a range which has not previously been associated with increased risk in the absence of proteinuria.
As noted, incorporation of cystatin C in addition to microalbuminuria allows the detection of a substantial number of older adults at increased risk of cardiovascular events (69% of individuals had either a cystatin C >1 mg/L, MA or both). We acknowledge that it remains to be determined whether these individuals have kidney disease per se. Ultimately, rather than labelling 69% of older adults with a disease, we should focus our efforts on understanding why the remaining 31% are at comparatively low risk.
The limitations of our study include the presence of only one sample of urine for ACR estimation; this level is known to vary considerably on a day-to-day basis. However, random fluctuations in ACR would have tended to bias our results to the null. Additionally, our estimates of kidney function are limited in that we do not have actual GFR measurements and so cannot comment on discrepancies between cystatin C or creatinine measurements and true GFR. Because urine samples were only collected at the seventh study visit, our study is subject to some degree of survivor bias; however, since the individuals who did not survive to the seventh study visit were sicker and had lower eGFR at baseline, we suspect that survivor bias would attenuate our findings.
In conclusion, we found independent risks of all-cause and cardiovascular mortality as well as incident CHF associated with both albuminuria and impaired kidney function as measured by cystatin C. Added risk was seen in those with abnormal cystatin C levels even in those without albuminuria. Abnormal cystatin C and albuminuria identify different segments of the population, and have useful, independent roles in providing prognostic information about future cardiovascular disease and mortality risk in older adults.