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Introduction: Cystatin C is a biomarker sometimes used as an alternative to serum creatinine when calculating eGFR and creatinine clearance (CrCl). Cystatin C is not confounded by muscle loss the way serum creatinine is, therefore, may be a better marker when calculating eGFR and CrCl for estimation of renal function and dosing medications. Prolonged critical illness affects the kidneys as well as skeletal muscle. Both are clinically linked as sites of serum creatinine generation and clearance and can lead to lower serum creatinine possibly overestimating calculated eGFR and CrCl. The purpose of this study is to compare serum creatinine eGFR and CrCl to cystatin C eGFR and CrCl and determine if this change would result in dose adjustments. Methods: A single-center, retrospective chart review was performed using the electronic medical record system at a 410-bed community tertiary care hospital. Patients admitted to the ICU with deconditioned states or prolonged critical illness who had a Cystatin C level ordered were included in the study. The primary outcome is the difference between serum creatinine eGFR and CrCl compared to cystatin C eGFR and CrCl. These values were then used to determine if this change would result in dose adjustments of medications. Results: 36 patients met inclusion criteria for analysis. All the patients had a deconditioned state with 33% of patients with BMI < 18 and 33% with BMI >40. The median calculated serum eGFR compared to Cystatin C eGFR was (108 vs 64, P = 0.009) and calculated serum CrCl compared to Cystatin C CrCl was (116 vs 37, P = 0.004). About 60% of patients would have required a medication dose adjustment based on the calculated Cystatin C CrCl compared to serum creatinine CrCl. Conclusions: Overall, patients had a significantly lower calculated Cystatin C eGFR and CrCl compared to serum creatinine eGFR and CrCl. The difference in these values would have led to additional dose reductions in medications for most patients. Based on this study, Cystatin C appears to be a better marker of renal function in deconditioned, critically ill patients, compared to serum creatinine when calculating eGFR and CrCl. Given the small sample size and retrospective nature of this evaluation, more robust studies are needed to confirm these findings.