Discussion
This case shows the importance of using CysC as an alternative or confirmatory marker compared with sCr to estimate GFR in patients with high muscle mass and/or high creatine intake, such as many in the US Department of Defense (DoD) and US Department of Veterans Affairs (VA) patient populations. In the presented case, recorded Cr levels climbed from baseline Cr with the initiation of bictegravir/emtricitabine/tenofovir alafenamide. This raised the concern that HIV treatment was leading to the development of kidney damage.22
Diagnosis of kidney disease as opposed to the normal decline of eGFR with age in individuals without intrinsic CKD requires GFR ≥ 60 mL/min/1.73 m2 with kidney damage (proteinuria or radiological abnormalities, etc) or GFR < 135 to 140 mL/min/1.73 m2 minus the patient’s age in years.23 The patient’s Cr peak at 1.83 mg/dL in 2018 led to an inappropriate diagnosis of kidney disease stage 3a based on an eGFRCr (2021 equation) of 52 mL/min/1.73 m2 when not corrected for body surface area.20 However, using the new 2021 equation using both Cr and CysC, the patient’s eGFRCr-Cys was 92 mL/min/1.73 m2 after a correction for body surface area.
The 2009 CKD-EPI recommended the calculation of eGFR based on SCr concentration using age, sex, and race while the 2021 CKD-EPI recommended the exclusion of race.3 Both equations are less accurate in African American patients, individuals taking medications that interfere with Cr secretion and assay, and patients taking creatine supplements, high daily protein intake, or with high muscle mass.7 These settings result in a decreased eGFRCr without corresponding eGFRCys changes. Using SCr and CysC together, the eGFRCr-Cys yields improved concordance to measured GFR across race groups compared to GFR estimation based on Cr alone, which can avoid unnecessary expensive diagnostic workup, inappropriate kidney disease diagnosis, incorrect dosing of drugs, and accurately represent the military readiness of patients. Interestingly, in African American patients with recently diagnosed HIV, CKD-EPI using both Cr and CysC without race inclusion led to only a 2.9% overestimation of GFR and was the only equation with no statistically significant bias compared with measured GFR.24
A March 2023 case involving an otherwise healthy 26-year-old male active-duty US Navy member with a history of excessive protein supplement intake and intense exercise < 24 hours before laboratory work was diagnosed with CKD after a measured Cr of 16 mg/dL and an eGFRCr of 4 mL/min/1.73 m2 without any other evidence of kidney disease. His CysC remained within normal limits, resulting in a normal eGFRCys of 121 mL/min/1.73 m2, indicating no CKD. His Cr and eGFR recovered 10 days after his clinic visit and cessation of his supplement intake. These findings may not be uncommon given that 65% of active-duty military use protein supplements and 38% use other performance-enhancing supplements, such as creatine, according to a study.25
Unfortunately, the BMP/CMP traditionally used at VA centers use the eGFRCr equation, and it is unknown how many primary care practitioners recognize the limitations of these metabolic panels on accurate estimation of kidney function. However, in 2022 an expert panel including VA physicians recommended the immediate use of eGFRCr-Cys or eGFRCys for confirmatory testing and potentially screening of CKD.26 A small number of VAs have since adopted this recommendation, which should lead to fewer misdiagnoses among US military members as clinicians should now have access to more accurate measurements of GFR.
The VA spends about $18 billion (excluding dialysis) for care for 1.1 to 2.5 million VA patients with CKD.27 The majority of these diagnoses were undoubtedly made using the eGFRCr equation, raising the question of how many may be misdiagnosed. Assessment with CysC is currently relatively expensive, but it will likely become more affordable as the use of CysC as a confirmatory test increases.5 The cost of a sCr test is about $2.50, while CysC costs about $10.60, with variation from laboratory to laboratory.28 By comparison, a renal ultrasound costs $99 to $140 for uninsured patients.29 Furthermore, the cost of CysC testing is likely to trend downward as more facilities adopt the use of CysC measurements, which can be run on the same analytical equipment currently used for Cr measurements. Currently, most laboratories do not have established assays to use in-house and thus require CysC to be sent out to a laboratory, which increases result time and makes Cr a more attractive option. As more laboratories adopt assays for CysC, the cost of reagents will further decrease.
Given such considerations, confirmation testing of kidney function with CysC in specific patient populations with decreased eGFRCr without other features of CKD can offer great medical and financial benefits. A 2023 KDIGO report noted that many individuals may be mistakenly diagnosed with CKD when using eGFRCr.3 KDIGO noted that a 2013 meta-analysis of 90,000 individuals found that with a Cr-based eGFR of 45 to 59 mL/min/1.73 m2 (42%) had a CysC-based eGFR of ≥ 60 mL/min/1.73 m2. An eGFRCr of 45 to 59 represents 54% of all patients with CKD, amounting to millions of people (including current and former military personnel).3,29-31 Correcting a misdiagnosis of CKD would bring significant relief to patients and save millions in health care spending.
Conclusions
In patients who meet CKD criteria using eGFRCr but without other features of CKD, we recommend using confirmatory CysC levels and the eGFRCr-Cys equation. This will align care with the KDIGO guidelines and could be a cost-effective step toward improving military patient care. Further work in this area should focus on determining the knowledge gaps in primary care practitioners’ understanding of the limits of eGFRCr, the potential mitigation of concomitant CysC testing in equivocal CKD cases, and the cost-effectiveness and increased utilization of CysC.