Cystatin C Is Ready for Clinical Use

Natalie Ebert; Michael G. Shlipak

Disclosures

Curr Opin Nephrol Hypertens. 2020;29(6):591-598. 

In This Article

Abstract and Introduction

Abstract

Purpose of Review: The goal of this update is to raise awareness of clinical scenarios where cystatin C has clear and immediate benefits as an alternative glomerular filtration rate (GFR) biomarker to supplement creatinine. An additional goal is to focus the estimated GFR (eGFR) controversy onto medication prescribing for agents with narrow therapeutic windows where better GFR estimation will lead to improved medical care.

Recent Findings: Equations that include cystatin C predict GFR more accurately than serum creatinine in children, adults, and older adults with larger effects among persons who are acutely ill. Numerous studies have evaluated medication dosing based on either GFR estimate; vancomycin was the most frequently studied drug and its target level and elimination were better predicted by cystatin C. Overall, approaches to medication dosing and monitoring that include cystatin C concentrations have been shown to result in a better achievement of drug trough levels. Furthermore, cystatin C offers the opportunity to avoid the race coefficient that is required for any current creatinine-based eGFR equation, which has been appropriately criticized for introducing unnecessary imprecision, assumptions and values on GFR estimation.

Summary: Hospital laboratories must make cystatin C available for clinical care to improve the safety and efficacy of medications that have narrow therapeutic windows.

Introduction

Cystatin C, a 13-kDa low molecular weight protein, is produced in all nucleated body cells at a constant rate, is freely filtered at the glomerulus, metabolized in the proximal tubulus and fulfills the criteria for a renal filtration marker.[1] 35 years ago, Dr Anders Grubb identified the value of cystatin C as an alternative marker for the assessment of glomerular filtration rate (GFR). In contrast to serum creatinine, the production rate of cystatin C has no relationship with muscle mass and is therefore unaffected by non-GFR determinants such as age, sex, and race. Cystatin C's independence of muscle mass is an extremely important advantage in clinical settings where cystatin C contributes important diagnostic information beyond the routinely measured creatinine-based estimated GFR (eGFR). Despite the advantages of cystatin C having been known for many years, it remains far from established as a routine marker in clinical practice.

In essentially all research studies, cystatin C has a stronger correlation than serum creatinine with measured GFR because of its more uniform production across populations, and this advantage of cystatin C usually persists despite the use of GFR equations that incorporate demographic coefficients as a proxy for creatinine production. Among GFR estimating equations, those with cystatin C have predicted GFR more accurately than serum creatinine in children,[2] adults[3] and older adults[4] with larger effects among persons who are acutely ill,[5] because creatinine generation is increasingly hard to predict with higher age and infirmity. In epidemiological studies, early stages of kidney function decline can be detected more readily by eGFR based on cystatin C[6] thus offering the opportunity to identify chronic kidney disease (CKD) earlier than when using creatinine-based eGFR. This improved approximation of GFR across the higher end of kidney function has resulted in cystatin C having far stronger associations than creatinine with long-term cardiovascular outcomes in numerous population-based cohort studies. Large-scale observational studies and a meta-analysis have demonstrated conclusively that cystatin C levels are more strongly associated with myocardial infarction, stroke, heart failure, frailty, end-stage renal disease, cardiovascular and all-cause mortality than creatinine, and these associations are detectable by cystatin C at eGFR thresholds of about 90 ml/min/1.73 m2 versus approximately 60 ml/min/1.73 m2 by creatinine[6–11] (Figure 1). The associations of kidney function measures and cardiovascular risk were found to be slightly weaker when cystatin C was combined with serum creatinine, compared with using cystatin C alone in the GFR equation. Also shown in Figure 1 is the reverse J-shaped association for the creatinine-based measurements of eGFR, with a significantly elevated risk of death at higher eGFR values, a result that was not found for cystatin C-based eGFR (Figure 1).

Figure 1.

Adjusted hazard ratios for death from any cause in the general-population cohort studies [8]. Hazard ratios for death from any cause, according to whether the estimated glomerular filtration rate was calculated with the measurement of creatinine, cystatin C, or both. The graphs show associations by plotting the adjusted hazard ratio versus the reference points, which are indicated by black diamonds (at 95 ml/min/1.73 m2 of BSA for death from any cause and death from cardiovascular causes and at 65 ml/min/1.73 m2 for end-stage renal disease). The hazard ratios were adjusted for age, sex, race, BMI, SBP, total cholesterol, presence or absence of a history of cardiovascular disease, smoking status, presence or absence of diabetes, and level of albuminuria. In each panel, solid circles indicate that the adjusted hazard ratio at the indicated estimated glomerular filtration rate level was significant, as compared with the reference point. For death from any cause, the meta-analysis included 11 general-population cohorts with 90 750 participants, of whom 12 351 died during follow-up.

Over the past 15 years, cystatin C's role has been relegated to its being an outstanding research tool for studying the epidemiology of kidney disease and its growing use as an outcome parameter in clinical trials. Yet, outside of certain countries like Sweden and China, cystatin C has had very little impact on routine patient care, which – in our view – is a lost opportunity.

The 2013 KDIGO guidelines had several statements that encouraged the use of cystatin C in routine clinical care. The strongest was a recommendation to use cystatin C – or to measure GFR with an exogenous filtration measure – when precision is required for medication dosing due to narrow therapeutic or toxic ranges for the drug, and in specific circumstances when eGFR based on serum creatinine may be less accurate due to low muscle mass.[12] For CKD staging the KDIGO guidelines currently suggest, rather than recommend, confirmatory testing with cystatin C-based eGFR for patients with stage 3a GFR (eGFR 45–60 ml/min/1.73 m2) who are without other manifestations of CKD such as microalbuminuria or macroalbuminuria. In a recent analysis on the clinical utility of cystatin C testing for managing CKD in older adults, Shardlow et al.[13] found that 59% of study participants with CKD stage 3a were restaged to a lower eGFR category indicating more severe CKD with cystatin C-based eGFR relative to the initial creatinine-based estimate. Although it is difficult to quantify the value of CKD reclassification in ambulatory patients, correct GFR staging from 3a to 5 has unquestionable impact on medication choices and dosing, patient education around their prognosis, and decisions for specialty referral and vascular access.

Other authors have further advocated for expanding the CKD guidelines around testing with cystatin C-based eGFR for those individuals with eGFR 60–90 ml/min/1.73 m2, particularly if they have additional risk factors for cardiovascular disease or are at risk for progressive CKD.[14] This question around CKD screening with cystatin C was not addressed by the 2012 KDIGO Guideline, but CKD screening will be a major focus of the upcoming KDIGO Controversy Conference Report on CKD Detection and treatment.

In our view, the focus on the potential importance of cystatin C measurement for the purpose of reclassification of CKD staging at the population level has led to interesting academic discussions that are important for the fields of epidemiology and public health. On the contrary, these debates have largely overshadowed the importance of accurate GFR estimation for individual patients and we believe that it is time to emphasize cystatin C's benefit in clinical care and to call upon laboratories to adapt their routine for diagnosing impaired kidney function. Of note, the same arguments for using cystatin C in clinical practice would apply to other alternative filtration markers that are under investigation.[15,16]

Our goal in this current review is to raise awareness of clinical use-cases where cystatin C has clear benefits as a second kidney GFR biomarker. We believe that ignoring the potential additional information gained by cystatin C testing leads to systematic overestimation of kidney function with adverse impacts on patient care. In addition to practicing clinicians, we hope this review will reach the audience of healthcare professionals working in the clinical laboratories and in clinical pharmacy. These teams must be informed about the importance of cystatin C measurement when treating acutely ill hospitalized patients, caring for children with potential kidney disease, and dosing potentially toxic medications in patients with abnormal muscle mass or prolonged inactivity. Furthermore, cystatin C also offers the opportunity to separate from the race coefficient that is required for any current creatinine-based eGFR equation, which has been appropriately criticized for introducing unnecessary imprecision, assumptions and values on GFR estimation.[17]

In medicine, new biomarkers may uncover important, previously hidden clues about diseases. Deeper knowledge about the state of an individual's disease through new biomarkers enables categorizing disease-subgroups and severity more accurately, and prescribing treatments with more precision. Over the last decade, the concept of individualized medicine has also been more widely used in the field of nephrology. Against this background, it is a mystery to us why there is still reluctance in the nephrology community to take advantage of cystatin C's benefits to improve patient care in contrast to the eagerness for new diagnostic approaches exhibited within other fields of medicine.

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