Cystatin C as a GFR Estimation Marker in Acute and Chronic Illness: A Systematic Review

Abstract

Rationale & objective: Creatinine-based GFR estimating (eGFRcr) equations may be inaccurate in populations with acute or chronic illness. The accuracy of GFR equations that use cystatin C (eGFRcys) or creatinine-cystatin C (eGFRcr-cys) is not well studied in these populations.

Study design: A systematic review of original articles identified from PubMed and expert sources. Two reviewers screened articles independently and identified those meeting inclusion criteria.

Setting & study populations: Adults and children with acute or chronic illness.

Selection criteria for studies: Studies published since 2011 that compared performance of eGFRcr, eGFRcys, and eGFRcr-cys relative to measured GFR (mGFR), used standardized assays for creatinine or cystatin C, and used eGFR equations developed using such assays. Studies of ambulatory clinical populations or research studies in populations with only CKD, kidney transplant recipients, only diabetes, kidney donor candidates, and community-based cohorts were excluded.

Data extraction: Data extracted from full text.

Analytical approach: Bias and percentages of estimates within 30% of mGFR (P₃₀) of eGFR compared with mGFR were evaluated.

Results: Of the 179 citations, 26 studies met the inclusion criteria: 24 in adults and 2 in children in clinical populations with cancer (n=5), HIV (n=5), cirrhosis (n=3), liver transplant (n=3), heart failure (n=2), neuromuscular diseases (n=1) critical illness (n=5), and obesity (n=2). In general, eGFRcr-cys had greater accuracy than eGFRcr or eGFRcys equations among study populations with cancer, HIV, and obesity, but did not perform consistently better in cirrhosis, liver transplant, heart failure, neuromuscular disease, and critical illness.

Limitations: Participants were selected because of concern for inaccurate eGFRcr, which may bias results. Most studies had small sample sizes, limiting generalizability.

Conclusions: eGFRcr-cys improves GFR estimation in populations with a variety of acute and chronic illnesses, providing indications for cystatin C measurement. Performance was poor in many studies, suggesting the need for more frequent mGFR.

Plain-language summary: Kidney function, specifically glomerular filtration rate (GFR), estimated using creatinine (eGFRcr) is often inaccurate in people with acute and chronic illness. The accuracy of estimates using cystatin C alone (eGFRcys) or together with creatinine (eGFRcr-cys) is not well studied in these populations. We conducted a systematic review to address the knowledge gap. Of the 179 papers reviewed, we identified 26 studies in clinical populations with cancer (n=5); HIV (n=5); cirrhosis (n=3); liver transplant (n=3); heart failure (n=2); neuromuscular disease (n=1); critical illness (n=5); and obesity (n=2). In general, eGFRcr-cys improved the GFR estimation in HIV, cancer, and obesity, providing indications for cystatin C measurement. Performance was poor in many studies, suggesting the need for more frequent measured GFR.

Keywords: Cystatin C; HIV; cancer; cirrhosis; creatinine; critical illness; glomerular filtration rate; heart failure; liver transplant; neuromuscular disease; obesity.

Figure 1

Bias creatinine and cystatin c estimating GFR equations by clinical population. Bias was defined as the median or mean difference between eGFR and mGFR (ie, eGFR − mGFR medium underestimate). Positive bias denotes overestimate and negative bias underestimate. ∗ Bias in study given as %Bias (ln). Units are mL/min/1.73m² for bias. (Green box) indicates small bias with magnitude of median difference of between −5 and +5 mL/min/1.73 m²; (yellow box) indicates medium underestimate as median difference of −5 to −10 mL/min/1.732m². (spotted yellow box) indicates medium overestimate as median difference of 5-10 mL/min/1.732m². Red box indicates large underestimate as median difference of less than −10 mL/min/1.732m² (ie, greater magnitude than less than −10). Spotted red box indicates large overestimate as median difference of greater than 10 mL/min/1.73 m². HSC, hematopoietic stem cell transplant; A, adult; C, children.

Figure 2

Accuracy of creatinine and cystatin C estimating GFR equations by clinical population. Accuracy was defined as the proportion of eGFR within 30% of mGFR (P₃₀). Where defined as 1-P₃₀, we converted it to P₃₀ for consistency. Units are percent for P₃₀. Green box indicates high accuracy with P₃₀ of magnitude > 90%. Yellow box indicates moderate accuracy with P₃₀ of magnitude 80%-90 %; (red box) indicates low accuracy with P₃₀ of magnitude less than 80%. GFR, glomerular filtration rate; mGFR, measured GFR; eGFR, estimated GFR.

Figure 3

GFR evaluation using initial and supportive tests. The algorithm describes the approach to the evaluation of GFR. Our approach is to use initial and supportive testing to develop a final assessment of true glomerular filtration rate (GFR) and to apply it in individual decision-making at each point in time. The initial test for evaluation of GFR is often eGFRcr, which will be available in most patients because creatinine is measured routinely as part of the basic metabolic panel. If the eGFRcr is expected to be inaccurate, or if a more accurate assessment of GFR is needed for clinical decision-making, such as diagnosis or staging of CKD or drug dosing, then cystatin C should be measured and the discordance between eGFRcr and eGFRcys should be assessed.^, If eGFRcr and eGFRcys are not discordant (within 15 mL/min/1.73 m² or 20%-30% of each other), then accuracy of eGFRcr, eGFRcys, and eGFRcr-cys is similar. If eGFRcr and eGFRcys are discordant (not within 15 mL/min/1.73 m² or 20%-30% of each other), then eGFRcr-cys is generally more accurate than either eGFRcr or eGFRcys, with some exceptions, such as otherwise healthy populations with increased creatinine generation owing to increased muscle mass, or decreased creatinine secretion or extra-renal elimination because of use of specific medications, when eGFRcys may be more accurate. If an even more accurate assessment of GFR is needed for a clinical decision, then GFR should be measured using plasma or urinary clearance of exogenous filtration markers, if available. This consideration should be applied to anytime GFR is required for a clinical decision. It is important to determine how accurate an assessment of GFR needs to be for a clinical decision. P₃₀ for eGFR does not generally exceed 90% (90% of eGFR within 30% of mGFR). P₁₅ for mGFR does not generally exceed 90% (90% of mGFR within 15% of true mGFR). At a GFR of 60 mL/min/1.73 m², 30% accuracy for eGFR corresponds to 42-78 mL/min/1.73 m² and 15% accuracy for mGFR corresponds to 51-69 mL/min/1.73 m². At a GFR of 30 mL/min/1.73 m², 30% accuracy for eGFR corresponds to 21-39 mL/min/1.73 m² and 15% accuracy for mGFR corresponds to 26-35 mL/min/1.73 m². ∗Use eGFRcr or eGFRcr-cys depending on discordance between eGFRcr and eGFRcys.