Charna Albert
October 2024—In patients at risk for chronic kidney disease, clinical practice guidelines released this year recommend the combined creatinine and cystatin C-based estimated glomerular filtration rate over the creatinine-based eGFR when cystatin C is available.
“Cystatin C isn’t perfect itself, but a combination of the two seems to hit the sweet spot,” Angela Ferguson, PhD, D(ABCC), said in a session at the ADLM meeting in July.
Dr. Ferguson is associate professor at the University of Missouri-Kansas City School of Medicine and co-director of clinical chemistry, director of immunology, and director of point-of-care testing in the Department of Pathology and Laboratory Medicine, Children’s Mercy Kansas City. The guidelines were released by the Kidney Disease: Improving Global Outcomes chronic kidney disease work group (Stevens PE, et al. Kidney Int. 2024;105[4S]:S117–S314).
When it comes to pediatric patients, said Darcy Weidemann, MD, MHS, Dr. Ferguson’s co-presenter and a pediatric nephrologist at Children’s Mercy, adding cystatin C to the estimating equations may lead to more precise estimates of GFR.
“Creatinine is a particularly poor marker of kidney function in patients with low muscle mass,” Dr. Weidemann said. “This is especially relevant in pediatrics, where use of creatinine alone can be misleading. Due to the unique developmental and growth considerations of a growing child, the ‘normal’ reference ranges are much wider in laboratory reference ranges, depending on how much they stratify out normal by age, and may not adequately cover the true spectrum of normal GFRs for a child of a particular age and size.” For example, she said, if a normal creatinine for an infant should be around 0.2, a value of 0.6 has a high risk of being missed as abnormal, “although that would be considered fairly significant impaired kidney function for a three-month-old baby.”
Cystatin C is particularly helpful at the higher GFR ranges, “where under-recognition of impaired kidney function is more likely using creatinine alone,” Dr. Weidemann said. “So that’s where a lot of the excitement about adding in cystatin C is, particularly in our pediatrics world—to improve that diagnosis.”
Dr. Ferguson in her talk reviewed three of the contemporary pediatric GFR estimating equations and described how she and her colleagues at Children’s Mercy implemented eGFR directly in the laboratory information system. Previously, the process required that the clinicians take values from the patient chart, plug them into online eGFR calculators, and transpose the information back into the electronic health record. The eGFR values were then saved in the notes section of the chart, apart from the other laboratory data. The nephrologists made a request of the laboratory: “Can you report the eGFR in the chart?” Which equation to use became the question for the laboratory.
Dr. Ferguson discussed the following three equations:
- Creatinine-based “bedside” CKiD equation (2009): eGFR = 41.3 × (height/SCr)
- Cystatin C-based equation (2012): eGFR = 70.69 × (cysC)-0.931
- Creatinine-cystatin C-based CKiD equation (2012): eGFR = 39.8 × [ht/SCr]0.456 × [1.8/cysC]0.418 × [30/BUN]0.079 × [1.076male] [1.00female] × [ht/1.4]0.179
A Children’s Mercy nephrologist was an investigator on a study that aimed to revisit the CKiD bedside equation (Pierce CB, et al. Kidney Int. 2021;99[4]:948–956). “This paper was in press at the time,” Dr. Ferguson said, “and we wanted to focus on the equations they were developing.” Using data from the Chronic Kidney Disease in Children Study, Pierce, et al., developed and validated four new eGFR equations for clinical use in children and young adults. The equations are referred to as the CKiD under 25 equations, or U25.
According to Pierce, et al., the data used to develop the original CKiD bedside equation came primarily from children aged eight to 15 and lacked an adequate sample of both young children under five and young adults 18 and over. “The purpose of their study was to include more patients and broaden the age range,” Dr. Ferguson said. Other study aims were to assess if the constant (K=41.3) for height/SCr should be modified by sex and age to yield less biased estimates of measured GFR—most notably in children under five and adults 18 to 25—and to develop a complementary estimating equation based on cystatin C, as well as compare the new equations with previously published eGFR equations for children and young adults.
The authors used 2,655 observations from 928 participants. For each marker, one equation used a sex-dependent K; in the other, K was sex- and age-dependent. GFR was measured directly by plasma iohexol disappearance. Use of an age-dependent K with ht/SCr models reduced average bias, notably in young children and young adults; age-dependent cystatin C models produced similar agreement to using a constant K in children under 18 years, but reduced bias in young adults. “They were able to improve the estimation of GFR, particularly in young children and young adults,” Dr. Ferguson said, as well as offer a single equation for use across the full pediatric age spectrum. “At our institution we take patients up to age 22,” she noted.
In Fig. 1 are the CKiD under 25 equations.
One caveat: “These equations were developed and validated in patients with mild to moderate CKD. It’s not recommended to use them in general screening because we don’t know the validity of these equations in the healthy patient,” Dr. Ferguson said.
“But the equations perform quite well,” she continued. “There’s an average bias in all age and sex subgroups within 10 percent of the measured GFR.” The age-dependent proposed equations, Pierce, et al., write, were evaluated alongside estimated GFRs from 11 other published equations for pediatrics and young adults. They add, “Only our proposed equations yielded non-significant bias and within 30% accuracy values greater than 85% in both the pediatric and young adult subpopulations.”
“One other point was made,” Dr. Ferguson said. “If you take eGFR-creatinine and eGFR-cystatin and average them, that gives you the best, most accurate estimation of GFR.” When the two estimates are available, Pierce, et al., write, the average of them preserves the unbiasedness, is more accurate and more precise than either of the single-marker estimates, and yields a sex- and age-dependent linear combination of the biomarkers as the estimate of GFR.
Cystatin C, a low-molecular-weight protein synthesized by all nucleated cells, functions as a cysteine protease inhibitor.
“It’s freely filtered by the glomerulus,” Dr. Ferguson said, and unlike creatinine, cystatin C concentration is unaffected by muscle mass, diet, age, or gender. It also has been shown to increase faster than creatinine when eGFR declines—80 mL/min/1.73m2 compared to 40 mL/min/1.73m2 for creatinine. “So that’s a pretty big difference in eGFR,” she said. The main issue with cystatin C is lack of assay standardization; though there is an international certified reference material, not all assay manufacturers have used it for calibration.
In Fig. 2 are the hazard ratios for adverse outcomes using the continuous model of eGFR. “These graphs are showing outcomes—all-cause mortality, cardiovascular, just a whole host of outcomes,” Dr. Ferguson said. Graph A shows the associations of eGFR based on creatinine alone with adverse outcomes. Graph B shows the associations of eGFR based on creatinine and cystatin C. “The eGFR-creatinine graph has more of a J-shaped curve,” she said. “It takes longer and the eGFR decreases more before you get an increase in hazard ratio. When eGFR is calculated with cystatin C and creatinine, it is much more linear and the hazard ratios increase at a lower amount of decrease of eGFR.”
