New Guidelines for Assessing Chronic Kidney Disease

Chronic kidney disease (CKD) is diagnosed and staged by measuring glomerular filtration rate (GFR), with a lower GFR indicating worse disease.^1,2 However, actual measurement of GFR is complicated, time-consuming, and rarely used in the clinic.^1,2 As an alternative, equations based on serum creatinine or cystatin C concentration, together with other variables, have been developed to estimate GFR (eGFR).

The inclusion of one variable—race—for eGFR was recently reevaluated by a Task Force formed by the National Kidney Foundation (NKF) and the American Society of Nephrology (ASN). They developed a new creatinine-based equation that is race-neutral.³ The Task Force also provided other recommendations, including the use of cystatin C to determine eGFR.³

This article will discuss CKD, the use of creatinine and cystatin C for calculating eGFR, and the race-neutral CKD-epidemiology collaboration (EPI) 2021 creatinine-based equation for calculating eGFR.

CKD: scope and risks

CKD affects about 37 million people in the United States (15% of adults), with about 90% not knowing they have it.⁴ The NKF estimates that around 80 million persons in the United States are at risk for developing CKD,⁵ and the risk of cardiovascular events and death increases with increasing CKD severity.⁶

CKD affects kidney structure and function but may not cause symptoms in its early stages. However, patients with CKD can develop end-stage renal disease (ESRD), need dialysis, and have higher risks for cardiovascular events and death.^2,6,7 Consequently, screening, diagnosing, and monitoring persons with CKD (see Sidebar), as well as those at high risk of developing CKD, are important for decreasing morbidity and mortality and improving overall outcomes.^2,8,9

Creatinine and cystatin C

eGFR, estimated using either creatinine- or cystatin C-based measurements, is most commonly used to diagnose CKD in clinical practice.

Creatinine

Creatinine is a breakdown product of creatine phosphate from muscle and protein metabolism. Because it is produced at a constant rate and is excreted via the kidneys, creatinine serum levels are routinely used to calculate an eGFR (both CKD-EPI 2021 equation as well as the prior 2009 equation).³ However, creatinine levels are influenced by diet and muscle mass. Consequently, eGFR may not accurately reflect GFR in certain patients, such as those who have serious comorbid conditions, have extremes of muscle mass (eg, bodybuilders, individuals who have had an amputation), are malnourished or obese, eat little or no meat, are taking creatinine dietary supplements, or are pregnant.^10,11 In addition, some medications can elevate serum creatinine level, including trimethoprim, fenofibrate, H2-blockers, and tyrosine kinase inhibitors.^10,11

Cystatin C

Cystatin C is a low molecular weight cysteine protease inhibitor that is produced by all nucleated cells and is removed from the bloodstream by glomerular filtration in the kidneys.^10,12 If kidney function and GFR decline, blood levels of cystatin C rise. An eGFR calculated using cystatin C may yield a more accurate eGFR for persons with unusually low or high muscle mass or protein intake because it is less influenced by these factors than is creatinine-based eGFR.^10,12-14 Notably, a recent study suggested that a cystatin C–based eGFR was a better predictor of adverse events (eg, all-cause mortality, progression to ESRD) than was a creatinine-based eGFR in older patients (>65 years old) with CKD.¹⁵

On the other hand, a cystatin C-based eGFR may be more affected by conditions such as thyroid disorders, corticosteroid use, smoking, diabetes, obesity, and inflammation.^16-18 Consequently, these factors should be considered when eGFR is determined using cystatin C.

CKD-EPI 2021 vs 2009 equations: eGFR and race

The CKD-EPI 2009 equation for eGFR is based on serum creatinine level and patient age, sex, and race.¹⁹ Results have been typically reported as “eGFR, African American” or “eGFR, non–African American”.³ However, eGFR results are, on average, 13% higher in Black individuals than in non–Black individuals, suggesting better kidney function.³ However, this approach may overestimate kidney function among Black individuals.^20-22 Importantly, because GFR is used to guide various treatments, drug dosing, and eligibility for kidney transplantation, a race-based calculation of eGFR may adversely impact Black Americans.^3,23 While they only make up about 13% of the population, Black Americans account for 35% of the people with kidney failure.⁴ Given that Black individuals account for a disproportionately high number of Americans who have kidney disease, the use of a race modifier in eGFR calculations may have contributed to major health disparities among this population.^23,24

In response to this potential disparity in healthcare, the NKF/ASN Task Force was assembled to evaluate the use of race in equations for determining eGFR.³

Considerations included:

• Assay standardization and availability
• Implementation of eGFR in practice
• Diversity of populations used in developing the equations
• Comparisons with measured GFR
• Clinical care, population tracking, and research consequences
• Patient centeredness

The Task Force concluded that not including race for determination of eGFR was most appropriate and recommended immediate implementation of the race-neutral CKD-EPI 2021 equation.³

Notably, a recent study found that eGFR equations that incorporate creatinine and cystatin C, but omit race, are more accurate and lead to smaller differences between Black individuals and non-Black individuals than CKD-EPI 2021 or cystatin C alone.²³

NKF ASN Task Force recommendations

The NKF ASN Task Force recently released 3 primary recommendations with respect to determining eGFR.³

Recommendation 1: The Task Force recommended that, for adults in the United States (>85% of whom have normal kidney function), the CKD-EPI 2021 equation based on serum creatinine level without the use of the race variable be implemented immediately in all laboratories.²⁵

Recommendation 2: The Task Force recommended national efforts to facilitate increased, routine, and timely use of cystatin C to determine eGFR. They recommend using cystatin C to confirm eGFR in adults who are at risk for, or have, CKD. The Task Force concluded that combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone.

Recommendation 3: The Task Force recommended encouragement and funding for further research on GFR estimation, with new endogenous filtration markers, and on interventions to eliminate race and ethnic disparities in kidney disease.

Potential unforeseen effects of the CKD-EPI 2021 equation

While the CKD-EPI 2021 equation provides an improved eGFR across all populations, it may adversely affect some patients. For example, race-neutral calculations could make some Black individuals ineligible for anticancer treatments that require a specific high eGFR for eligibility.^1,22

Assessing kidney damage and function

CKD is defined as an abnormality of kidney structure or function for >3 months that can adversely affect health; the primary diagnostic criterion is decreased GFR.^1,2 CKD may also be diagnosed based on markers of kidney damage, such as histological abnormalities, structural abnormalities, abnormal urine sediment, tubular disorder–caused electrolyte abnormality, or an increased urinary albumin level (albuminuria).^1,2

The presence of albuminuria indicates increased glomerular permeability, which is characteristic of CKD and an indication of kidney damage.^1,2 Albuminuria is determined by calculating the urine albumin-creatinine ratio (ACR) or by measuring total urinary albumin excretion over 24 hours.^1,2 A urine ACR ≥30 mg/g (albumin excretion rate ≥30 mg/24 hours) is diagnostic of albuminuria (30 to 300 mg/g was formerly referred to as microalbuminuria, and >300 mg/g as macroalbuminuria).^1,2

Proteinuria (urinary total protein-creatinine ratio ≥150 mg/g) may indicate increased glomerular permeability and CKD but can also be seen in other conditions (eg, myeloma).^1,2

Management of CKD: eGFR and ACR

An eGFR <60 mL/min/1.73 m² for >3 months and/or urine ACR ≥30 mg/g for >3 months indicates the presence of CKD.^1,2 An eGFR and ACR provide a “kidney profile” recommended by the NKF for diagnosing and managing CKD in at-risk patients.^1,6,8 Importantly, the results are independent risk predictors of major adverse cardiovascular events (myocardial infarction or stroke).²⁶

The frequency of eGFR monitoring in patients with CKD is based on the risk of disease progression as assessed using eGFR and urine ACR (kidney profile).¹ For a summary for recommended monitoring frequencies, please refer to

Laboratory Testing for Chronic Kidney Disease Diagnosis and Management.

In addition, the Kidney Failure Risk equation (KidneyFailureRisk.com) uses ACR and eGFR to estimate the risk of persons developing CKD and progressing to ESRD.

How the laboratory can help

Quest Diagnostics offers tests and panels for diagnosis and management of CKD. Test offerings range from health screenings for abnormal eGFR, proteinuria, and albuminuria, to tests for management of CKD, its comorbidities, and its complications.

More information about CKD is available at

• QuestDiagnostics.com/Test/Test-Guides/TG_CKD/Laboratory-Testing-for-Chronic-Kidney-Disease-Diagnosis-and-Management?p=r
• QuestDiagnostics.com/Test/Test-Guides/TS_Cystatin_eGFR/?p=tg
• QuestDiagnostics.com/Test/Test-Guides/TS_KidneyProfile/?p=tg

References

1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3(1):1-150. doi:10.1038/kisup.2012.76

2. Kalantar-Zadeh K, Jafar TH, Nitsch D, et al. Chronic kidney disease. Lancet. 2021;398(10302):786-802. doi:10.1016/S0140-6736(21)00519-5

3. Delgado C, Baweja M, Crews DC, et al. A unifying approach for GFR estimation: recommendations of the NKF-ASN Task Force on reassessing the inclusion of race in diagnosing kidney disease. Am J Kidney Dis. 2021:S0272-6386(21)00828-3. doi:10.1053/j.ajkd.2021.08.003

4. Chronic kidney disease in the United States, 2021. Centers for Disease Control and Prevention. Published March 4, 2021. Accessed January 5, 2022. https://www.cdc.gov/kidneydisease/pdf/Chronic-Kidney-Disease-in-the-US-2021-h.pdf

5. Kidney disease: the basics. National Kidney Foundation. Accessed January 5, 2022. https://www.kidney.org/news/newsroom/factsheets/KidneyDiseaseBasics

6. National Kidney Foundation Laboratory Engagement Advisory Group. Laboratory engagement plan: transforming kidney disease detection. National Kidney Foundation and ASCP. Published February 2018. Accessed January 5, 2022. https://www.ascp.org/content/docs/default-source/get-involved-pdfs/istp-ckd/laboratory-engagement-plan.pdf

7. Chu CD, McCulloch CE, Banerjee T, et al. CKD awareness among US adults by future risk of kidney failure. Am J Kidney Dis. 2020;76(2):174-183. doi:10.1053/j.ajkd.2020.01.007

8. Vassalotti JA, Centor R, Turner BJ, et al. Practical approach to detection and management of chronic kidney disease for the primary care clinician. Am J Med. 2016;129(2):153-162.e7. doi:10.1016/j.amjmed.2015.08.025

9. Shlipak MG, Tummalapalli SL, Boulware LE, et al. The case for early identification and intervention of chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2021;99(1):34-47. doi:10.1016/j.kint.2020.10.012

10. Pasala S, Carmody JB. How to use… serum creatinine, cystatin C and GFR. Arch Dis Child Educ Pract Ed. 2017;102(1):37-43. doi:10.1136/archdischild-2016-311062

11. Shahbaz H, Gupta M. Creatinine clearance. In: StatPearls [Internet]. StatPearls Publishing; 2021. https://www.ncbi.nlm.nih.gov/books/NBK544228/

12. Benoit SW, Ciccia EA, Devarajan P. Cystatin C as a biomarker of chronic kidney disease: latest developments. Expert Rev Mol Diagn. 2020;20(10):1019-1026. doi:10.1080/14737159.2020.1768849

13. Gounden V, Bhatt H, Jialal I. Renal function tests. In: StatPearls [Internet]. StatPearls Publishing; 2021. Updated July 20, 2021. Accessed January 5, 2022.  https://www.ncbi.nlm.nih.gov/books/NBK507821/

14. NICE Guideline Updates Team (UK). Evidence reviews for cystatin C based equations to estimate GFR in adults, children and young people. In: Chronic kidney disease: Evidence review M. National Institute for Health and Care Excellence (NICE); 2021. https://www.ncbi.nlm.nih.gov/books/NBK574725/

15. Tavares J, Santos J, Silva F, et al. Association between severe chronic kidney disease defined by cystatin-c and creatinine and clinical outcomes in an elderly population - an observational study. J Bras Nefrol. 2021;43(2):165-172. doi:10.1590/2175-8239-JBN-2020-0092

16. Shlipak MG, Matsushita K, Ärnlöv J, et al. Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med. 2013;369(10):932-943. doi:10.1056/NEJMoa1214234

17. Stevens LA, Schmid CH, Greene T, et al. Factors other than glomerular filtration rate affect serum cystatin C levels. Kidney Int. 2009;75(6):652-660. doi:10.1038/ki.2008.638

18. Levey AS, Coresh J, Tighiouart H, et al. Measured and estimated glomerular filtration rate: current status and future directions. Nat Rev Nephrol. 2020;16(1):51-64. doi:10.1038/s41581-019-0191-y

19. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-612. doi:10.7326/0003-4819-150-9-200905050-00006

20. Vyas DA, Eisenstein LG, Jones DS. Hidden in plain sight—reconsidering the use of race correction in clinical algorithms. N Engl J Med. 2020;383(9):874-882. doi:10.1056/NEJMms2004740

21. Eneanya ND, Yang W, Reese PP. Reconsidering the consequences of using race to estimate kidney function. JAMA. 2019;322(2):113-114. doi:10.1001/jama.2019.5774

22. Casal MA, Ivy SP, Beumer JH, et al. Effect of removing race from glomerular filtration rate-estimating equations on anticancer drug dosing and eligibility: a retrospective analysis of National Cancer Institute phase 1 clinical trial participants. Lancet Oncol. 2021;22(9):1333-1340. doi:10.1016/S1470-2045(21)00377-6

23. Inker LA, Eneanya ND, Coresh J, et al. New creatinine- and cystatin C-based equations to estimate GFR without race. N Engl J Med. 2021;385(19):1737-1749. doi:10.1056/NEJMoa2102953

24. Inserro A. Flawed racial assumptions in eGFR have care implications in CKD. Am J Man Care. Published October 25, 2020. Accessed January 5, 2022. https://www.ajmc.com/view/flawed-racial-assumptions-in-egfr-have-care-implications

25. Miller WG, Kaufman HW, Levey AS, et al. National Kidney Foundation Laboratory Engagement Working Group recommendations for implementing the CKD-EPI 2021 race-free equations for estimated glomerular filtration rate: practical guidance for clinical laboratories. Clin Chem. 2021:hvab278. doi:10.1093/clinchem/hvab278

26. Currie CJ, Berni ER, Berni TR, et al. Major adverse cardiovascular events in people with chronic kidney disease in relation to disease severity and diabetes status. PLoS One. 2019;14(8):e0221044. doi:10.1371/journal.pone.0221044

Published date: Mar 2022