Prognostic Role Of Serum Cystatin C In Heart Failure: Systematic Review And Meta-analysis

Background Heart failure (HF) is the leading cause of morbidity and mortality in the United States. With the recent advances in HF management leading to increased life expectancy, renal dysfunction is a common accompaniment. Cystatin C, a cysteine protease inhibitor, has been shown to be a more sensitive marker of early kidney injury than creatinine or eGFR. Also, cystatin C has been studied for its predictive role in cardiovascular diseases beyond kidney function. We executed a systematic review to assess the role of cystatin C in mortality, hospital readmissions, and worsening renal failure (WRF) among HF patients. Methods We conducted a systematic review and meta-analysis to compare levels of serum cystatin C between 1) HF patients who died and who survived, 2) HF patients who reached composite endpoint (mortality and readmission) and who did not 3) HF patients who had WRF compared with who did not. We included peer-reviewed English language articles from PubMed and EMBASE published up to December 1, 2021. We analyzed the association of serum cystatin C with the outcomes mentioned earlier using a random-effects meta-analysis. We assessed publication bias using funnel plots. Results Among 683 articles, 67 (prospective and retrospective cohort studies) met the inclusion criteria with an aggregate of 26,343 participants. Sixty-one studies were included in the quantitative analysis. Fifty-six studies reported an association of serum cystatin C levels with mortality and composite endpoint, and eight studies studied WRF. Patients who died had higher pooled mean serum cystatin C levels [pooled mean differences (pMD) 0.42, 95% CI 0.31 to 0.53 mg/L, p<0.001] compared to the patients who survived. Patients with composite outcomes had higher pooled mean serum cystatin C levels [pMD 0.38, 95% CI 0.28 to 0.47, P<0.001]. Patients with WRF, when compared to patients without WRF, did not have a significant difference in pooled mean serum cystatin C [pMD 0.37, 95%CI -0.01, 0.75 mg/L]. Higher serum cystatin C levels carried a higher hazard for mortality [hazard ratio (HR) 1.59, 95% CI 1.42-1.77] and composite outcomes [HR 1.49, 95% CI 1.23-1.75]. Serum cystatin C had an AUC of 0.76 (95%CI, 0.74-0.78) for mortality and 0.68 (95%CI, 0.65-0.72) for composite endpoint. Serum cystatin C was not a significant predictor of WRF [HR 1.03, 95%CI, 0.79-1.26] with an AUC of 0.66 (95%CI, 0.56-0.77)(Figure1). None of the above analyses showed statistically significant publication bias. Conclusions We found that serum cystatin C is associated with significant mortality and composite endpoint in HF patients. Serum cystatin C was a significant predictor of WRF in HF patients. Heart failure (HF) is the leading cause of morbidity and mortality in the United States. With the recent advances in HF management leading to increased life expectancy, renal dysfunction is a common accompaniment. Cystatin C, a cysteine protease inhibitor, has been shown to be a more sensitive marker of early kidney injury than creatinine or eGFR. Also, cystatin C has been studied for its predictive role in cardiovascular diseases beyond kidney function. We executed a systematic review to assess the role of cystatin C in mortality, hospital readmissions, and worsening renal failure (WRF) among HF patients. We conducted a systematic review and meta-analysis to compare levels of serum cystatin C between 1) HF patients who died and who survived, 2) HF patients who reached composite endpoint (mortality and readmission) and who did not 3) HF patients who had WRF compared with who did not. We included peer-reviewed English language articles from PubMed and EMBASE published up to December 1, 2021. We analyzed the association of serum cystatin C with the outcomes mentioned earlier using a random-effects meta-analysis. We assessed publication bias using funnel plots. Among 683 articles, 67 (prospective and retrospective cohort studies) met the inclusion criteria with an aggregate of 26,343 participants. Sixty-one studies were included in the quantitative analysis. Fifty-six studies reported an association of serum cystatin C levels with mortality and composite endpoint, and eight studies studied WRF. Patients who died had higher pooled mean serum cystatin C levels [pooled mean differences (pMD) 0.42, 95% CI 0.31 to 0.53 mg/L, p<0.001] compared to the patients who survived. Patients with composite outcomes had higher pooled mean serum cystatin C levels [pMD 0.38, 95% CI 0.28 to 0.47, P<0.001]. Patients with WRF, when compared to patients without WRF, did not have a significant difference in pooled mean serum cystatin C [pMD 0.37, 95%CI -0.01, 0.75 mg/L]. Higher serum cystatin C levels carried a higher hazard for mortality [hazard ratio (HR) 1.59, 95% CI 1.42-1.77] and composite outcomes [HR 1.49, 95% CI 1.23-1.75]. Serum cystatin C had an AUC of 0.76 (95%CI, 0.74-0.78) for mortality and 0.68 (95%CI, 0.65-0.72) for composite endpoint. Serum cystatin C was not a significant predictor of WRF [HR 1.03, 95%CI, 0.79-1.26] with an AUC of 0.66 (95%CI, 0.56-0.77)(Figure1). None of the above analyses showed statistically significant publication bias. We found that serum cystatin C is associated with significant mortality and composite endpoint in HF patients. Serum cystatin C was a significant predictor of WRF in HF patients.