Acute kidney injury is among the most morbid complications of cardiac surgery. Not only does AKI lead to a higher in-hospital mortality risk, but it also predisposes to long-term mortality risk, even among persons who appear to recover from the AKI episode.18–19
In this large, multi-center, prospective study, we compared the ability of pre-surgical measurement of serum cystatin C, an alternative marker of kidney filtration, with the clinical standard of serum creatinine to risk-stratify for post-surgical AKI. Although the post-surgical definition of clinical AKI is based on the magnitude of rise in the serum creatinine level, pre-surgical cystatin C levels had much stronger and more linear associations with AKI risk than pre-surgical serum creatinine. Furthermore, for the AKI outcome, cystatin C had a relevant improvement in risk discrimination, as demonstrated by a significant absolute increase in the c-statistic of 6%, and a substantial improvement in reclassifying individuals to low, intermediate, and high risk for AKI. Therefore, cystatin C may have a useful role for pre-surgical stratification among high-risk, adult cardiac surgery patients.
Although cystatin C has been clinically available for several years and is FDA-approved as an alternative test of kidney function, it has not found widespread use or a specific clinical indication. Several studies in various settings have determined that cystatin C has much stronger associations with cardiovascular and other clinical outcomes in ambulatory patients,20–22
but prognostic value in the outpatient setting has not translated into routine clinical use. Since kidney function is an integral determinant of in-hospital outcomes, cystatin C could potentially have utility for risk stratification in the inpatient setting. One recent study of 150 patients from three academic medical centers found that cystatin C was better than creatinine for predicting post-surgical AKI using the same definition as in our study; however, perhaps related to their sample size, cystatin C only increased the c-statistic by 1%.23
Another study found that cystatin C had much stronger associations than creatinine with clinical outcomes among patients hospitalized with acute coronary syndrome.24
In our study, we observed an improvement in risk discrimination for the AKI outcome; a 6% increase in the c-statistic is a moderate difference for a single biomarker as is a NRI of 21%.17
However, the odds ratios and improvements in the c-statistic for severe AKI were smaller. It may be that the development of severe AKI is more dependent upon intra-surgical characteristics (e.g., long cardiopulmonary bypass time, intra-surgical hypotension) rather than pre-surgical variables, including pre-surgical kidney function. In addition, the smaller number of severe AKI outcomes may have limited the ability of kidney function markers to change the c-statistic, but the odds ratios for each kidney measure were also much weaker for severe AKI. In future studies, this cohort should combine with other large studies to generate a more powerful evaluation of whether cystatin C can improve risk discrimination for the less common outcomes of severe AKI and in-hospital death.
The value of these research findings must be appreciated in the context of the important role risk assessment has in cardiac surgery. Several sophisticated algorithms have been developed, including the STS tool used throughout the U.S., to generate a pre-surgical likelihood for the patient to survive cardiac surgery.10,25
These tools are used in part to allow individual patients to balance the risks and benefits of cardiac surgery, but they have even greater importance for monitoring the quality of care and outcomes of cardiac surgery by individual surgeons and hospitals. Due to the intense scrutiny on cardiac surgery outcomes, even mild improvements to help risk adjust for adverse outcomes could have great clinical importance. Since pre-existing chronic kidney disease is generally accepted as one of the strongest risk factors for AKI and death,7,10,26–27
finer ascertainment of pre-surgical kidney function would help improve risk-assessment of patients undergoing cardiac surgery. One recent study has suggested that AKI risk should be an important factor for patients weighing the choice between cardiac surgery or percutaneous coronary intervention.28
Therefore, if cystatin C can be validated further as a relevant marker for improving risk assessment for AKI or other adverse outcomes after cardiac surgery, then it could be of value to individual patients, clinicians, and hospitals.
The major strength of this study is that it is the largest, multi-center study to date to compare cystatin C and creatinine as measures of pre-surgical kidney function for determination of post-surgical AKI risk. The diverse settings of the six institutions ensured a broad inclusion of high-risk cardiac surgery patients. However, this study does have important limitations. Although our study had a very large number of AKI cases, we had few patients with either dialysis-requiring AKI (n=12) or who died (n=19). Therefore, the ability of these kidney biomarkers to predict risk for these outcomes could not be reliably assessed in our study. In the future, we will assess long-term survival and kidney function after cardiac surgery in this cohort, and we will compare the predictive value of pre-surgical creatinine and cystatin C measures. Another limitation is that 5% of pre-surgical visits occurred more than 30 days prior to surgery; however, only two patients had a pre-surgical visit more than three months prior to surgery. In these patients, it is possible that kidney function might have changed during the interval prior to surgery. The overall discrimination for AKI in this study was moderate, indicated by c-statistics of 0.71 and 0.74 for AKI and severe AKI, respectively. We believe that risk stratification was limited in our study, in part because we specifically recruited a cohort at increased risk for AKI. In addition, we did not have a validation set for our study, so confirmation will require future investigation in other settings. Furthermore, despite the multi-center design of our study, two-thirds of participants were men and over 90% were white. Finally, we relied on blood-based markers of kidney function that are easily measured in clinical care, rather than a criterion standard of measured GFR.
In conclusion, we found that pre-surgical cystatin C levels had a stronger and more linear association with AKI risk than serum creatinine or eGFR based on serum creatinine, the clinical standards. For the outcome of AKI, cystatin C impressively improved risk discrimination based upon changes in the c-statistic of the ROC curve and by reclassifying categories of AKI risk. If confirmed in other studies, cystatin C may have importance for pre-surgical risk stratification among potential high-risk surgical candidates.