We performed a systematic review to examine the utility of CysC level measurement for the early diagnosis of CI-AKI in patients undergoing CAG or PCI. The research was conducted in PubMed, Web of Science, and Scopus from January 2020 to March 2025 using the Advanced Search Builder feature. Search words were used in the [Title OR Abstract] fields. It was limited to original articles in English only, and specific words and phrases and medical subject headings (MeSH) terms for each database were used, for example: ‘(Cystatin C) AND (Acute Kidney Injury OR Nephropathy OR Acute Renal Injury OR Contrast Induced Nephropathy OR Contrast Induced Acute Kidney Injury) AND (Angiography OR Percutaneous Coronary Intervention OR Percutaneous Coronary Revascularization OR Coronary Intervention OR Coronary Revascularization OR Cardiac Catheterization)’.

This systematic review included original studies that examined the effectiveness of CysC level measurement for early CI-AKI detection in patients undergoing cardiac catheterization, such as CAG or PCI. Studies have reported CI-AKI or contrast induced nephropathy (CIN) as a consequence of the catheterization procedure. Additional relevant literature was identified from the reference lists of the selected studies. Both retrospective and prospective studies, as well as blinded and non-blinded studies, were considered. The exclusion criteria included studies involving participants on renal replacement therapy who had received contrast medium within two days prior to enrollment, had contrast medium allergies, or had undergone aortic valve replacement, renal transplantation, or heart transplantation. Patients with acute heart failure, severe valvular disease, or left ventricular thrombus were also excluded. The review did not include case reports or series with few patients, review articles without original data, editorials, letters, or conference papers.

Two researchers (AM and OC) examined the titles and abstracts. After applying inclusion and exclusion criteria, relevant information was extracted from the selected studies to meet the survey’s requirements.

Reviewing reference lists from previously published review articles led to the inclusion of pertinent studies. We identified seven eligible research articles in their final published form. We extracted only the principal findings relevant to this review’s scope for specific articles. Data extraction tables compiled from the information from the selected articles are presented in Table 1 (Ref. [14, 18, 19, 20, 21, 22, 23]).

Two authors (AM and APK) independently assessed the quality of the published interventions. A third author (HS) resolved any disagreements. To determine the possibility of bias in each of the evaluated studies, the QUADAS-2 instrument was used to evaluate the population, technique, analysis, and reporting requirements of each study [24]. The assessment tool was divided into four key areas: flow and timing, reference standards, index tests, and patient selection. For each individual study, these areas were classified as “low”, “high”, or “unclear”. Following this, classifications across all areas were displayed, accompanied by a subjective evaluation of the overall quality of the studies under consideration.

After conducting a thorough search, we found 410 articles from January 2020 to March 2025. We removed 79 articles, leaving us with 331 studies to screen based on their titles and abstracts. After screening, we excluded 269 studies and were left with 62 to assess their full texts. In total, seven studies met the inclusion criteria for our systematic review. The selection process for these studies is presented in Fig. 1. We extracted data from seven eligible articles, and summarized the information in Table 1.

Fig. 1.

PRISMA flow diagram for enrollment of studies.

Fig. 2 evaluates the risk of bias across various domains for the evaluated studies. The overall risk of bias of all evaluated investigations were low. However, Luo et al. [19] and Abood et al. [21] had some concerns regarding the index test domain.

Fig. 2.

Quality assessment and bias risk assessment in the investigations included in the systematic review.

The primary population targeted was patients who underwent PCI or CAG. Overall, the evaluated studies had 2642 participants with an age range of 18 to 92 years. Two hundred-four patients developed CI-AKI. There was only one article (Gu et al. [14]) in which all participants had normal kidney function. In all studies, at least CysC and SCr were evaluated. Researchers have also assessed various other biomarkers including serum neutrophil gelatinase-associated lipocalin (NGAL), B-type natriuretic peptide (BNP), C-C motif chemokine ligand 14 (CCL14), C-reactive protein (CRP), interleukin-18 (IL-18), osteopontin, and kidney injury molecule 1 (KIM-1). However, due to the aim of our review study, we focus on the level of CysC for early prediction of CI-AKI. All investigations except one evaluated the pre- and post-procedure level of CysC. Budano et al. [22] just evaluated the CysC level 24 hours before the procedure.

In 2022, Gu et al. [14] presented a study on 341 PCI patients with initially normal renal function. They identified preoperative CysC levels $>$1.03 mg/L as related to an increased risk of CIN, with an impressive difference in preoperative CysC between CI-AKI and non-CI-AKI groups. In contrast, SCr presented no such distinction, indicating the promise of CysC in detecting renal damage before SCr rises. In 2024, Mahmood et al. [23] demonstrated the excellent diagnostic and predictive ability of CysC and CCL14 in 88 patients who were undergoing PCI, with area under the curve (AUC) $>$0.99 by high sensitivity and specificity using pre-procedure (cut-off 15 ng/mL) and 48-h post-procedure (cut-off 17 ng/mL) values. Similarly, Luo et al. [19] found that 24-hour CysC and NGAL post-PCI had slightly higher diagnostic sensitivity (AUC = 0.88) than SCr (AUC = 0.856) in 300 patients. However, sample size limitations and cut-off values were reported. In 2020, Budano et al. [22] assessed 713 CAG participants and considered that a single baseline CysC measurement was not only a stronger predictor (AUC = 0.82) of CI-AKI compared to SCr or glomerular filtration rate (GFR) from SCr but also long-term adverse outcomes at 10 years, suggesting a 1.4 mg/L cut-off value that efficiently excluded CI-AKI and pointed towards greater cardiovascular risk. Pilčević et al. [18] compared CysC and SCr in 45 patients with chronic kidney disease (CKD) after CAG. They reported that CysC identified CI-AKI significantly more frequently (42.22% vs. 8.89%) at 24 hours, reflecting CysC’s higher sensitivity and proposing a 10% increase in CysC as a reliable early diagnostic marker. However, there is disagreement because another study by Abood et al. [21] with 41 patients reported divergent results, showing SCr concentrations significantly increased at 24 hours following contrast in the CIN group but not in the level of CysC. So they concluded that SCr was the better early biomarker in their sample. In summary, all studies except one demonstrated that measuring the CysC level (pre- or post-procedure) was better than SCr for the early identification of CI-AKI. However, the mean cut-off value of the CysC for early detection of CI-AKI was variable in studies.

CysC is a protein with a low molecular weight of 122 amino acids and a molecular weight of 13 kDa, garnering increasing attention. It is classified as a cysteine proteinase inhibitor of the type 2 family [25]. Cystine proteases irreversibly break down peptide bonds within amino acid sequences, significantly impacting apoptosis, lipid metabolism, immunological responses, cell control, and cell proliferation and adhesion [9].

The majority of cysteine proteinase inhibitors belong to the superfamily of cystatins. They are widely dispersed throughout animals and allow control over the degradation of extracellular and intracellular proteins. They are, therefore, essential for maintaining the proper ratio of free cysteine proteinases to their inhibitory complexes. Its quantities have been connected to several other illnesses because it enables them to regulate against detrimental cysteine proteinase activities. All nucleated cells synthesize CysC, encoded by the housekeeping C3T3 gene, at a comparatively steady pace. It is widely dispersed and present in most bodily fluids, including plasma [26, 27].

Due to its unique physical and molecular characteristics, CysC is being considered as a potential kidney function indicator. One of its key features is its constant production rate, which remains unaffected by muscle mass. This, along with its reabsorption and catabolization by proximal renal tubular cells, and its relatively free filtration by glomeruli, makes it a promising candidate for kidney function assessment [28].

CI-AKI is a serious clinical issue after invasive cardiac interventions, playing a major role in the increased length of hospital stay, high healthcare costs, and negative patient outcomes, such as enhanced morbidity and mortality. Given the substantial impact of contrast media on the incidence of AKI in hospital settings, the clinical significance of CI-AKI warrants considerable attention [29]. The incidence of CI-AKI after primary PCI varies widely, from 4% to 28%, based on the type and amount of contrast medium administered and the particular diagnostic criteria applied. Intermittent intravenous injection of iodinated contrast media during CAG and PCI inevitably increases the risk of nephrotoxicity [30]. With limited universally effective prophylactic measures, detection of CI-AKI, especially in high-risk patient groups, is crucial [15]. Consequently, much research has been directed towards assessing potential early detection biomarkers, among which CysC has been an avid focus of study.

Our systematic review synthesizes robust evidence regarding the clinical utility of pre-procedure CysC concentration as a predictive biomarker of CI-AKI occurrence. In some studies, preoperative CysC levels were better predictors than conventional preoperative SCr levels. Gu et al. [14] reported that, among 341 patients with initially normal renal function undergoing PCI, preoperative CysC $>$1.03 mg/L was strongly associated with an increased risk of CIN. Notably, while baseline SCr values did not differ significantly between patients who developed CIN and those who did not, the corresponding preoperative CysC values were significantly different (p 0.01). This observation suggests that CysC can unveil subclinical renal dysfunction or vulnerability that is not readily detectable by SCr measurements alone. Confirming these observations, Budano et al. [22] investigated a larger population (n = 713) undergoing CAG and showed the prognostic value of baseline CysC. Their study established significant validity for CysC in the prediction of CI-AKI, with an AUC of 0.82, which was greater than that for SCr (AUC = 0.70) and SCr-based GFR estimates (AUC = 0.75). Additionally, they demonstrated that a CysC cut-off level of 1.4 mg/L was strongly predictive (97% negative predictive value) for excluding CI-AKI and independently predicted cardiovascular mortality in the long term. Likewise, Mahmood et al. [23] observed very high pre-procedural predictive accuracy for CysC with an AUC of 0.999 while studying 88 patients undergoing scheduled elective PCI with baseline normal renal function. The cut-off value suggested by them of 15 ng/mL had a 97.7% sensitivity and 100.0% specificity. Despite the heterogeneity in the analytical methods and cut-off values reported among studies, an evolving consensus is apparent: pre-procedural CysC levels are important for risk stratification prior to contrast media exposure.

Regarding the diagnostic potential of post-procedural CysC levels, several studies suggest that CysC enables earlier detection of renal damage than the traditional marker, SCr. Luo et al. [19], in their investigation of 300 post-PCI patients, determined that 24-hour CysC was very accurate diagnostically (AUC = 0.874). This was comparable to NGAL (AUC = 0.885) and better than SCr (AUC = 0.856). In a different group of 45 patients with pre-existing CKD who had undergone CAG, Pilčević et al. [18] noted markedly greater incidences of CI-AKI when CI-AKI was defined as CysC increase versus SCr increase at the 24-hour time point (42.22% vs. 8.89%, p 0.001). Based on this discordance, they hypothesized that a modest 10% increase in CysC at 24 h would be an important early diagnostic criterion and that conventional SCr-based definitions are not adequately sensitive in the early post-procedural period. Mahmood et al. [23] also provided evidence of the diagnostic usefulness of CysC after the procedure, with the outcome being 48-hour CysC levels that had an AUC of 0.992 for CI-AKI diagnosis. However, this is a later time than that investigated in other studies.

Nonetheless, a definitive consensus regarding the superiority of CysC as an early diagnostic marker remains elusive. Abood et al. [21] reported conflicting findings in a smaller investigation involving 41 patients. Their results suggested that the change in SCr level at 24 hours was more indicative of CIN development than the corresponding change in CysC. Specifically, they observed no statistically significant elevation in CysC levels within the CIN subgroup (n = 6) at 24 hours post-contrast administration, whereas SCr levels did increase significantly. This observation challenges the notion that CysC universally rises earlier or more substantially than SCr in all instances of CIN within the initial 24-hour window. The discrepancy between the findings of Abood et al. [21] and those of other researchers may potentially be attributable to the limited statistical power inherent in their study, particularly given the very small number of participants who developed CIN, which could constrain the generalizability of their conclusions.

Based on the comprehensive analysis conducted in our systematic review, pre-procedural CysC appears to possess greater efficacy and reliability for predicting CI-AKI risk compared to post-procedural CysC measurements for early diagnosis. The evidence corroborating the predictive value of preoperative CysC exhibits greater consistency across diverse studies and generally demonstrates superior performance relative to traditional SCr measurements for patient risk stratification. While postoperative CysC also shows promise for the early diagnosis of CI-AKI, the findings exhibit greater heterogeneity, with at least one study presenting divergent results. A distinct advantage of measuring CysC preoperatively lies in its capacity to identify individuals at elevated risk before contrast exposure, thereby enabling the potential implementation of targeted preventive strategies in those deemed most vulnerable to CI-AKI.

Overall, CysC emerges as a clinically relevant biomarker for both risk stratification and early diagnosis of CI-AKI following cardiac interventions involving contrast media. Preoperative CysC levels, in particular, demonstrate substantial predictive potential. Future research initiatives should prioritize the establishment of standardized cut-off values, the optimization of measurement timing relative to contrast exposure, and the validation of these findings within larger, more heterogeneous patient cohorts. Such efforts are crucial to enhance and optimize the clinical implementation of CysC assessment in the management of this prevalent iatrogenic complication.

SCr level is currently the most commonly examined indicator of renal function. It is released into the bloodstream from the muscle tissue, resulting in a relatively stable rate of entry and individual plasma concentration that varies based on muscle mass, sex, and age. SCr is not attached to plasma proteins, passes freely through the glomeruli, and is minimally reabsorbed by the proximal tubules. However, these tubules secrete small quantities of SCr in the urine. As plasma SCr levels rise, tubular secretion increases, which can lead to an inaccurate overestimation of the GFR in the Rehberg test for patients with moderate to severe reductions in kidney function (50 mL per minute) [31]. Some studies have shown that CysC-based GFR equations more closely approximate measured GFR compared to SCr-based equations, particularly in certain patient populations like stable kidney transplant recipients [32].

While both SCr and CysC are affected by factors unrelated to GFR, CysC is influenced by fewer variables and to a lesser extent than SCr. SCr levels fluctuate according to factors such as age, sex, muscle mass, exercise, diet, and protein consumption. In contrast, CysC is affected by a different set of non-GFR factors, including systemic inflammation, obesity, thyroid disorders, and steroid use [33, 34].

Additionally, CysC decreases before SCr in patients with AKI, allowing for an earlier prediction of renal recovery. This makes CysC a more sensitive indicator of the early stages of kidney impairment. In patients with heart failure, CysC has shown better predictive value than SCr for adverse outcome prediction. It may identify individuals at higher risk of kidney disease progression than SCr alone would detect [35].

Although CysC provides these benefits, it is crucial to acknowledge that it is not without its drawbacks. As was previously noted, a few factors can affect CysC. Furthermore, the widespread implementation of CysC testing encounters multiple challenges, such as lower familiarity among clinicians and a higher cost than SCr. In practical applications, the most comprehensive evaluation of kidney function may be achieved by combining CysC and SCr, particularly in cases where SCr-based estimates may be suspect. This method can improve the accuracy of estimating GFR and stratifying risk in different clinical settings [9, 12, 36]. Table 2 summarizes the comparison of the CystiC and SCr for the diagnosis of CI-AKI.