Unveiling the Untapped Potential: Cystatin C Testing in Kidney Function Assessment

The burden of Chronic Kidney Disease (CKD) remains a growing public health problem. In 2019, the worldwide prevalence was estimated at 7.2 to 13.4%, with CKD incidence, prevalence, mortality and disability-adjusted life years having risen by at least 20% from 2007 through 2017 [1]. In the United Kingdom (UK), adult patients starting Kidney Replacement Therapy (KRT) for End Stage Renal Disease (ESRD) in 2021 had increased by 7.3% with diabetes remaining the most common identifiable Primary Renal Disease (PRD) accounting for 31.3% of patients [2]. Public Health England (PHE) prevalence modelling predicts that 2.6 million people aged 16 and older are living with CKD stages 3 to 5, both diagnosed and undiagnosed. Between 2011 and 2036, this prevalence is expected to increase to 4.2 million, 8.3% [3].

Precise determination of renal function through the estimation of Glomerular Filtration Rate (eGFR) has long been a holy grail of measurement. The “gold standard” use of endogenous markers such as inulin and iohexol are invasive, time consuming and not appropriate for routine clinical use. Since 1940, this role has fallen to creatinine, a heterocylic nitrogenous product of creatine metabolism. Over the years, numerous iterations of equations for eGFR have been developed and adopted on a global scale, with creatinine establishing a monopoly and general acceptance as the “best we can do.”

However, cystatin C, a low molecular weight, 122-amino acid protein has been on the radar since its discovery in 1961. As with fashion, interest has peaked and troughed over the years but now is the time it should be taken seriously as the prime candidate to either be used in combination with, or completely replace creatinine. Unlike its counterpart, creatinine, cystatin C maintains a near constant rate of production, is freely filtered by glomeruli, almost completing reabsorbed and metabolised in the renal tubules and remains unaffected by muscle mass variations. These unique characteristics make it a more attractive endogenous candidate for assessing kidney function, challenging the conventional reliance on creatinine.

Laboratory assays for measurement of cystatin C have improved significantly. Predominantly carried out through Particle-Enhanced Immunoassays like Turbidometric Immunoassay (PETIA) or Nephelometric Immunoassay (PENIA). The swift turnaround time and minimal interference from external substances make cystatin C testing an efficient and reliable method for kidney function estimation. Introduction of a reference material for cystatin C in 2014 has further improved this endogenous marker.

Equations for estimated GFR were first developed by Cockroft and Gault in 1976 who correlated creatinine clearance with measured GFR. Further work led to more reliable equations; the MDRD6 and MDRD7 equations. Next, the Chronic Kidney Disease Epidemiology Collaboration published CKD-EPI. More recently, in 2020, the European Kidney Function Consortium (EKFC) published an equation with an extended age range from 2 to 90 years, and in 2021, CKD-EPI was modified removing the modification factor based on race.

One of the standout features of cystatin C is its independence from race or genetic ancestry, a significant departure from creatinine. Recent recommendations from the National Kidney Foundation and American Society of Nephrology advocate for increased use of cystatin C to estimate kidney function, recognizing its ability to provide more accurate assessments across diverse populations [4].

Studies have demonstrated the superiority of cystatin C-based eGFR in predicting clinical outcomes compared to creatinine-based estimates [5-8]. This is particularly pronounced in elderly populations, where cystatin C emerges as a robust and independent risk factor for mortality [5]. Ethnicity is a further advantage of cystatin C, in a large study of South Asian individuals, cystatin C identified over five times the number of participants with decreased estimated GFR compared to creatinine [6]. This highlights the potential for cystatin C testing to identify high-risk ethnic groups where traditional markers may fall short. The burden of cardiovascular disease in chronic kidney disease is another area where cystatin C outshines creatinine. Elevated cystatin C concentrations have been consistently linked to adverse cardiovascular outcomes, including death, heart failure, stroke, and myocardial infarction [7,8].

It is possible to combine cystatin C with creatinine (eGFRcreat-cys), this equation enhances the accuracy of GFR estimation and improves the classification of chronic kidney disease. Combining these markers allows for a more sensitive and accurate estimation of GFR which is crucial in identifying subtle changes in renal function.

The combination of eGFR cystatin and eGFR creatinine facilitates better risk stratification. The dual assessment helps in identifying individuals who may benefit from closer monitoring and targeted interventions. There is the potential to alleviate some burden on healthcare systems, reduce unnecessary referrals, and focus efforts on individuals at the highest risk [9].

Selective glomerular hypofiltration syndrome may not manifest with overt symptoms or changes in routine creatinine-based assessments. It is hypothesized that alterations in the size and function of glomerular filtration pores, reducing filtration of ‘medium-sized’ molecules (5-30kDa) might explain a reduction in eGFR cystatin/creatinine ratio [10].

However, despite its potential benefits, routine cystatin C testing faces obstacles. The cost, accessibility, and the level of clinical awareness remain significant challenges. Cystatin C testing is approximately ten times more costly than creatinine testing, posing financial constraints for widespread adoption [11]. Moreover, the availability of national assay services lags behind the demand, hindering the implementation of guidelines recommending cystatin C testing [12]. Finally, there is an educational deficit and clinicians will need time to become familiar with cystatin C testing and interpreting the results.

In conclusion, cystatin C remains at the crossroads of revolutionizing kidney function assessment. Its unique properties and superior predictive abilities make it a compelling alternative to traditional markers like creatinine. While challenges in cost and accessibility persist, the potential benefits, especially in identifying high-risk populations and enhancing cardiovascular risk prediction, make cystatin C testing a promising candidate for more accurate and inclusive kidney function assessments.

The unique responses of cystatin C and creatinine to glomerular changes aid in differentiating the underlying causes of glomerular dysfunction. As we seek to identify patients developing chronic kidney disease earlier and improving our prediction models for their mortality and morbidity, the research spotlight should turn to cystatin C, prompting a re-evaluation of our current practices and a renewed commitment to exploring its potential.

1. Kidney Disease Improving Global Outcomes (KDIGO). Controversies Conference on Early Identification & Intervention in CKD. 2019.
2. UK Renal Registry (UKRR). 25th Annual Report. 2021.
3. Public Health England (PHE). Chronic Kidney Disease Prevalence Model. 2014.
4. Delgado C, Baweja M, Crews DC, Eneanya ND, Gadegbeku CA, Inker LA, Mendu ML, Miller WG, Moxey-Mims MM, Roberts GV, St Peter WL, Warfield C, Powe NR. A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. J Am Soc Nephrol. 2021 Dec 1;32(12):2994-3015. doi: 10.1681/ASN.2021070988. Epub 2021 Dec 1. PMID: 34556489; PMCID: PMC8638402.
5. Shlipak MG, Wassel Fyr CL, Chertow GM, Harris TB, Kritchevsky SB, Tylavsky FA, Satterfield S, Cummings SR, Newman AB, Fried LF. Cystatin C and mortality risk in the elderly: the health, aging, and body composition study. J Am Soc Nephrol. 2006 Jan;17(1):254-61. doi: 10.1681/ASN.2005050545. Epub 2005 Nov 2. PMID: 16267155.
6. Chen DC, Lees JS, Lu K, Scherzer R, Rutherford E, Mark PB, Kanaya AM, Shlipak MG, Estrella MM. Differential Associations of Cystatin C Versus Creatinine-Based Kidney Function With Risks of Cardiovascular Event and Mortality Among South Asian Individuals in the UK Biobank. J Am Heart Assoc. 2023 Feb 7;12(3):e027079. doi: 10.1161/JAHA.122.027079. Epub 2023 Jan 25. PMID: 36695320; PMCID: PMC9973614.
7. Lees JS, Rutherford E, Stevens KI, Chen DC, Scherzer R, Estrella MM, Sullivan MK, Ebert N, Mark PB, Shlipak MG. Assessment of Cystatin C Level for Risk Stratification in Adults With Chronic Kidney Disease. JAMA Netw Open. 2022 Oct 3;5(10):e2238300. doi: 10.1001/jamanetworkopen.2022.38300. PMID: 36282503; PMCID: PMC9597396.
8. Lees JS, Welsh CE, Celis-Morales CA, Mackay D, Lewsey J, Gray SR, Lyall DM, Cleland JG, Gill JMR, Jhund PS, Pell J, Sattar N, Welsh P, Mark PB. Glomerular filtration rate by differing measures, albuminuria and prediction of cardiovascular disease, mortality and end-stage kidney disease. Nat Med. 2019 Nov;25(11):1753-1760. doi: 10.1038/s41591-019-0627-8. Epub 2019 Nov 7. Erratum in: Nat Med. 2020 Aug;26(8):1308. PMID: 31700174; PMCID: PMC6858876.
9. Peralta CA, Shlipak MG, Judd S, Cushman M, McClellan W, Zakai NA, Safford MM, Zhang X, Muntner P, Warnock D. Detection of chronic kidney disease with creatinine, cystatin C, and urine albumin-to-creatinine ratio and association with progression to end-stage renal disease and mortality. JAMA. 2011 Apr 20;305(15):1545-52. doi: 10.1001/jama.2011.468. Epub 2011 Apr 11. PMID: 21482744; PMCID: PMC3697771.
10. Malmgren L, Öberg C, den Bakker E, Leion F, Siódmiak J, Åkesson A, Lindström V, Herou E, Dardashti A, Xhakollari L, Grubb G, Strevens H, Abrahamson M, Helmersson-Karlqvist J, Magnusson M, Björk J, Nyman U, Ärnlöv J, Ridefelt P, Åkerfeldt T, Hansson M, Sjöström A, Mårtensson J, Itoh Y, Grubb D, Tenstad O, Hansson LO, Olafsson I, Campos AJ, Risch M, Risch L, Larsson A, Nordin G, Pottel H, Christensson A, Bjursten H, Bökenkamp A, Grubb A. The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation. J Intern Med. 2023 Mar;293(3):293-308. doi: 10.1111/joim.13589. Epub 2022 Dec 7. PMID: 36385445; PMCID: PMC10107454.
11. Shardlow A, McIntyre NJ, Fraser SDS, Roderick P, Raftery J, Fluck RJ, McIntyre CW, Taal MW. The clinical utility and cost impact of cystatin C measurement in the diagnosis and management of chronic kidney disease: A primary care cohort study. PLoS Med. 2017 Oct 10;14(10):e1002400. doi: 10.1371/journal.pmed.1002400. PMID: 29016597; PMCID: PMC5634538.
12. Chen DC, Potok OA, Rifkin D, Estrella MM. Advantages, Limitations, and Clinical Considerations in Using Cystatin C to Estimate GFR. Kidney360. 2022 Aug 23;3(10):1807-1814. doi: 10.34067/KID.0003202022. PMID: 36514729; PMCID: PMC9717651.