Cystatin C—a biomarker for the early risk assessment of renal impairment

Kidney disease has become a huge global health crisis, increasing healthcare costs, mortality, and morbidity rates. The global prevalence of chronic kidney disease (CKD) has continued to rise during a short timespan. In 2016, 10 percent of the global population were identified as having CKD. The highest prevalences were reported in Europe, the Middle East, East Asia, and Latin America, estimated at 12 percent and the lowest prevalence in South Asia, estimated at seven percent.¹

Early risk assessment of renal function is vital. In 1990, CKD was ranked as the 27th leading cause of death in the Global Burden of Disease study,² moving up to 18^th in 2010³, 13^th in 2013², and 12^th by 2015. From 2005-2015, the overall CKD mortality rate increased by 31.7 percent, and accounted for 1.1 million deaths globally in 2015.⁴ The CKD burden can be attributed to obesity and diabetes. Globally, the prevalence of diabetic kidney disease rose by 39.5 percent between 2005 and 2015, coinciding with the increased CKD prevalence.⁴ Fortunately, CKD can be prohibited and progression halted or slowed with early diagnosis and treatment.³

Traditional CKD testing methods

The modern classification of kidney function is based on estimated GFR (eGFR), which classifies CKD in five stages.⁵ In 2004, the UK’s National Institute for Health and Care Excellence (NICE) updated the classification of CKD to include the albumin:creatinine ratio (ACR) which indicates the level of proteinuria. This aids in the risk stratification of patients, as testing based on eGFR alone can produce falsely low eGFR results in patients with near-normal function.⁶

The most commonly used screening test for renal impairment is creatinine. When testing for CKD using creatinine, certain factors must be taken into consideration, including: age, gender, ethnicity, and muscle mass. Interestingly, black men and women will present with higher creatinine levels compared to white men and women, respectively.⁷

It has been noted that serum creatinine is not an adequate screening test for renal impairment in the elderly (65 years of age and over) due to their decreased muscle mass. As a result, these patients may be misdiagnosed with severe renal failure, resulting in suboptimal care.⁸

In 2011, a review of CKD biomarkers found that proteinuria is the most sensitive marker of CKD progression, especially when used with eGFR. However, an earlier and more sensitive biomarker is required.⁹

The main disadvantage of using creatinine to screen for renal impairment is that up to 50 percent of renal function can be lost before significant creatinine levels become detectable—as creatinine is insensitive to small changes in GFR. Consequently, treatment may not be provided in a timely fashion, which can be fatal. Therefore, an earlier and more sensitive biomarker for renal function is vital.¹⁰

Clinical significance of Cystatin C

Cystatin C is a small (13 kDa) cysteine proteinase inhibitor, produced by all nucleated cells at a constant rate. Cystatin C travels through the bloodstream to the kidneys where it is freely filtered by the glomerular membrane, resorbed, and fully catabolized by the proximal renal tubes. As a result, Cystatin C is an ideal biomarker of GFR function.¹¹

Numerous key publications have recently advocated the testing of Cystatin C in clinical settings:

1. Clinical evaluation of serum Cystatin C and creatinine in patients with chronic kidney disease: a meta-analysis (2013)¹²

The meta-analysis study searched a number of sites, including, China National Knowledge Infrastructure databases, PubMed, Google Scholar, and Cochrane Library to identify randomized controlled trials that determine the diagnostic value of Cystatin C and creatinine, for estimating GFR in patients with CKD. Seventeen studies met this inclusion criteria totalling 2,521 patients with CKD. The meta-analysis study found that Cystatin C was more specific than creatinine in estimating GFR.

2. Serum Cystatin C as a marker of renal function in detection of early acute kidney injury (2013)¹³

This study assessed 200 healthy subjects, and 130 subjects with acute kidney injury (AKI). The study examined serum creatinine and serum Cystatin C levels in the AKI subjects to establish the relevance of both creatinine and Cystatin C in the early stages of AKI. The study found that 56.2 percent of the AKI subjects had normal creatinine levels, however, Cystatin C levels were elevated, which is referred to as the ‘creatinine blind range.’ Therefore, Cystatin C levels are elevated long before creatinine levels begin to rise. As such, Cystatin C is a more sensitive marker for AKI compared to creatinine and Cystatin C, which does not have a blind area.

3. Chronic kidney disease in adults: assessment and management (2015)¹⁴

NICE updated their CKD assessment and management guidelines in adults, recommending Cystatin C testing due to its higher specificity for significant disease outcomes than those based on creatinine. eGFRcystatinC measurements will also significantly reduce the number of patients being misdiagnosed as having renal disease, thus reducing the overall CKD burden. NICE also recommend using eGFRcystatinC when a patient has an eGFcreatinine of 45 to 53 ml/min/1.73 m2, sustained for a minimum of 90 days, and no proteinuria or other marker of present kidney disease.

4. Cystatin C is indispensable for evaluation of kidney disease (2017)¹⁵

A systematic literature search found 3,500 investigations into Cystatin C as a marker of GFR. These investigations concluded that Cystatin C should be an integral part of the analysis spectrum for the optimal evaluation of CKD as Cystatin C isn’t dependent on body composition, unlike creatinine where muscle mass is a strong influencer.
The studies concluded that eGFRcystatinC was significantly superior than eGFRcreatinine, however, using both improves GFR estimations.

REFERENCES

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2. Bikbov, Boris. Chronic kidney disease: impact on the global burden of mortality and morbidity. The Lancet. [Online] 2015.
3. National Kidney Foundation. Global Facts: About Kidney Disease. National Kidney Foundation. [Online] National Kidney Foundation, 2015.
4. Neuen Brendon Lange, et al. Chronic kidney disease and the global NCDs agenda. s.l. : BMJ Global Health, 2017.
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8. Swedko Peter J., et al. Serum Creatinine is an Inadequate Screening Test for Renal Failure in Elderly Patients. Research Gate. [Online] February 2003. [Cited: 6 May 2018.]
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12. Zhang M., et al. Clinical evaluation of serum cystatin C and creatinint in patients with chronic kidney disease: a meta-analysis. NCBI. [Online] 04 August 2013. [Cited: 19 April 2018.]
13. Nephrol Indian J. Serum cystain C as a marker of renal function in detection of early acute kidney injury. NCBI. [Online] 23 May 2013. [Cited: 19 April 2018.] 
14. National Institute for Health and Care Excellence. Chronic kidney disease in adults: assessment and management: 2 Implementation: getting started. NICE. [Online] January 2015. [Cited: 19 April 2018.]
15. Grubb Anders. Cystatin C is Indispensable for Evaluation of Kidney Disease. NCBI. [Online] 28 December 2017. [Cited: 19 April 2018.]