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In this pre-specified secondary analysis of the STOP-ACEi trial (1-2), we explored the impact of stopping or continuing renin angiotensin system (RAS) inhibitor therapy in people with advanced CKD on serum cystatin C levels.
Cystatin C is a low molecular weight protein produced at a constant rate by nucleated cells and relatively freely filtered by glomeruli (3). Studies have shown cystatin C outperforms creatinine as a marker of true kidney function and has been demonstrated to have an increased sensitivity and accuracy for changes in true GFR (4). NICE and KDIGO guidelines do not currently recommend routine cystatin C measurement, and only endorse confirmation testing in specific circumstances when the eGFRcreat is less accurate (5-6).
The use of RAS inhibitors including ACE inhibitors and angiotensin-receptor blockers (ARB) has been shown to reduce cystatin C levels in a handful of small studies (7-11). In people with CKD, serum cystatin C levels have been shown to be a more reliable predictor of cardiovascular outcomes and risk of progression to end stage kidney failure (ESKF) than serum creatinine, as well as identifying more people who are at increased risk such as elderly and non-white ethnic groups (12-16).
Cystatin C values were obtained at baseline, 12, 24 and 36 months. We excluded samples obtained after the initiation of kidney-replacement therapy (KRT). Primary analysis used complete case analysis and mixed-effects linear regression model, adjusting for minimization variables, baseline value, time-point, and treatment by time interaction.
Sensitivity analysis was conducted using a pattern mixture model to account for missing data that was not at random. To model the longitudinal cystatin C data with time-to-event data, a joint model was utilized which incorporated the cystatin C measurements at various time points and accounted for the occurrence of KRT or ESKF.
Primary Analysis
Cystatin-C
Time point
Summary Statistic
STOP
Continue
Mixed-effects linear regression
Mean Diff (95% CI)
P-value
Treatment by time interaction p-value
mg/L
Baseline
N
183
181
Our results demonstrate significant differences in cystatin C levels between discontinue and continue study arms, particularly at 24 months. Sensitivity analyses support these findings and provide additional insights by accounting for missing data and the impact of KRT and transplantation.
The findings from this secondary analysis suggest eGFRcys has value in advanced CKD. Overall, this research emphasizes the value of cystatin C as a marker of kidney function in advanced CKD and raises questions regarding cystatin C as a treatment target for people with CKD.