In this prospective cohort of community dwelling older adults, we observed an association between rapidly declining kidney function (loss of eGFR >3 mL/min/1.73 m2 per year) and elevated risk for all-cause and cardiovascular mortality. These associations with elevated risk were observed regardless of the initial eGFR. Rapid decline by either eGFRcreat or eGFRcys was associated with elevations in mortality risk, and these associations were similar across subgroups of age, sex, race, cardiovascular disease, and baseline risk status.
While CKD is a well-established risk factor for all-cause and cardiovascular mortality, loss of kidney function within a population with relatively well-preserved kidney function has not previously been associated with adverse outcomes. One prior study 21
examined progression to CKD over 13 years of follow-up among a cohort of 281 individuals with hypertension and baseline eGFR higher than 90 mL/min/1.73 m2
; the authors noted an association, albeit without controlling for level of baseline eGFR, between progression to CKD and future cardiovascular disease events. It is noteworthy that this was a select population with a known risk factor for progression, whereas the CHS population was substantially larger, more heterogeneous, and more generalizable to the general population of older adults.
There are several reasons why loss of kidney function may be associated with increased mortality risk. Ongoing decline in kidney function may play a causal role by exacerbating cardiovascular disease risk factors such as hypertension and dyslipidemia or by causing retention of inflammatory solutes leading to oxidative stress and vascular damage. In addition, worsening kidney function may lead to decreased appetite, loss of lean body mass, decreased physical function, and overall frailty.22,23
Alternatively, loss of kidney function may be a marker of global atherosclerotic disease progression, with vascular disease leading to multi-organ dysfunction—including that in the kidneys—and predisposing to higher mortality risks.
Rapid decline measured by eGFRcreat and eGFRcys were both associated with adverse outcomes. Overall, eGFRcys detected more individuals with decline in kidney function in this cohort than did eGFRcreat, possibly reflecting that cystatin C is more sensitive to small changes in eGFR. However, participants with only eGFRcreat rapid decline also had elevated mortality risk, which implies that change in eGFRcys has imperfect sensitivity for detecting high-risk individuals. Individuals with rapid decline in kidney function detected by both measures had the highest risk (nearly 10% annual mortality rate), suggesting that the 2 measures may provide complementary risk assessment in older adults.
Although the CHS comprises a community-based, representative sample of older adults in the US, the individuals included in this analysis were selected for having survived long enough to have at least 2 measures of kidney function. These participants were healthier and had better kidney function on average than the full CHS cohort, so their magnitude of decline in kidney function was likely less than would have been observed in the overall cohort. Nevertheless, even in this healthier subgroup, there was substantial variability in kidney function loss over time, and rapid declines of kidney function were strongly associated with mortality risk.
Our study has several limitations. We do not have direct measurements of GFR and therefore cannot assess whether the changes we observed in eGFR by either cystatin C or creatinine are truly reflective of changes in kidney function. Because 85% of the black subjects in this study were added to the cohort after the first measurement of cystatin C and creatinine, most had only 2 measurements of creatinine level; thus, we cannot determine change in eGFR as accurately in this population. Albuminuria was not measured at baseline in CHS, so we cannot comment on the role of this marker of kidney disease in mediating or modifying the relationships we observed. While regression to the mean may have led to misclassification bias, we considered several different statistical adjustments for baseline kidney function to account for this and noted that our results were robust regardless of the method used. Although cystatin C appears to be a very sensitive marker of kidney function, it may be affected by thyroid dysfunction, corticosteroid use, and body composition, and cystatin C measurements may not reflect actual GFR as accurately at the extremes of body mass.24,25
In addition, we cannot determine whether the association of rapid kidney decline with mortality risk is causal or rather a marker of other physiologic processes that impact the kidney and other organs. Despite adjustment in multivariate models for both hypertension and diabetes mellitus, we cannot exclude the possibility of residual confounding from lifetime exposure to these conditions. However, we observed similar associations with increased mortality for the subgroup without hypertension, diabetes mellitus, or cardiovascular disease, suggesting that residual confounding was unlikely to be the primary explanation for our findings.
There are several potential implications of the results. First, decline in kidney function exceeding 3 mL/min/1.73 m2 per year is independently associated with adverse outcomes. Second, changes in serum creatinine and cystatin C levels appear to provide complementary information in older adults, with the 2 measures capturing overlapping subgroups at increased mortality risk. Third, these findings were robust across multiple subgroups, including level of baseline kidney function. These associations should be confirmed in other cohorts of older adults as well as in other populations at risk for kidney disease progression. Recognition of early loss of eGFR may be important as a prognostic tool in older adults regardless of their baseline comorbid conditions.