Serum cystatin C for estimation of GFR

CASE

An 80-year-old man with type 2 diabetes and hypertension was referred to the nephrology clinic for assessment of persistent hyperkalemia despite discontinuation of his angiotensin-converting enzyme inhibitor. The patient was frail, sedentary, and had a body mass index of 37 kg/m². Select blood testing results are shown in Table 1. His estimated glomerular filtration rate (eGFR) was calculated using 3 equations that incorporated creatinine (eGFRcr), cystatin C (eGFRcys) and both creatinine and cystatin C (eGFRcr-cys), as shown in Table 2.

Table 1.

Patient’s Laboratory Testing Results

Potassium, mEq/L	5.9	3.3–4.8
Bicarbonate, mEq/L	22	24–32
Creatinine, mg/L	1.15	0.6–1.3
Cystatin C, mg/L	1.84	<1.23
Urinary albumin-to-creatinine ratio (ACR), mg/g	504	<30

Table 2.

Patient’s eGFR values and Chronic Kidney Disease (CKD) Stage

	eGFR	CKD Stage
eGFRcr	64	G2A3
eGFRcys	32	G3bA3
eGFRcr-cys	44	G3bA3

Units of eGFR are ml/min/1.73m². eGFR calculated using CKD-EPI equations without race¹.

HOW DO YOU INTERPRET THESE TEST RESULTS?

1. The eGFRcr may be inaccurate because the patient is frail and sedentary.

2. The eGFRcr of 64 ml/min/1.73m² indicates normal kidney function.

3. The eGFRcys may be low because of patient has decreased muscle mass.

4. The eGFRcys may be reduced because the patient has type 2 diabetes.

Discussion

Answer

A. The eGFRcr may be inaccurate because the patient is frail and sedentary.

Test characteristics

Chronic kidney disease (CKD) is typically defined as GFR < 60 ml/min/1.73m² or urinary ACR > 30 mg/g that is present for 3 months or more.² Accurate assessment of GFR and albuminuria is important to determine the presence, stage, and prognosis of CKD, and to inform important treatment decisions, such as when to initiate hemodialysis or consider kidney transplant. In 2021, the National Kidney Foundation and American Society of Nephrology Task Force encouraged all US clinical laboratories to adopt the CKD Epidemiology Collaboration (CKD-EPI) 2021 eGFR equations without race,² which were developed and validated using large, diverse populations.^3,4

eGFRcr is the most commonly used equation to estimate GFR. Creatinine is a non-protein nitrogenous metabolic product of creatine phosphate, derived from skeletal muscle and dietary intake of cooked meat. Creatinine is useful for estimating GFR because it is released into the bloodstream at a relatively constant rate and is filtered by the kidneys. However, serum creatinine can be influenced by factors other than kidney function. Low muscle mass, low activity levels, vegetarian diet, and conditions such as frailty, lower extremity amputation, advanced heart failure or liver failure, are associated with lower serum creatinine levels and cause eGFRcr to be higher than actual GFR.⁵ Conversely, serum creatinine levels may be higher in very muscular individuals, resulting in an eGFRcr that is lower than actual GFR³. Recent ingestion of cooked meat and use of medications that inhibit proximal tubule secretion of creatinine (such as trimethoprim, dronedarone, cimetidine and tyrosine kinase inhibitors) can elevate serum creatinine, leading to a reduction in eGFRcr that is not due to a true decrease in kidney filtration function⁵.

Use of serum cystatin C is recommended by the 2021 National Kidney Foundation and American Society of Nephrology Task Force to estimate GFR in adults with CKD or at risk for CKD.^3,4 Serum cystatin C is a low molecular weight protein found in all tissues in the body. It is filtered at the glomerulus and not secreted into the renal tubules or reabsorbed into the bloodstream. Although not affected by muscle mass or diet, determinants of cystatin C levels are less well understood. However, obesity, hypothyroidism, cigarette smoking and use of systemic corticosteroids are associated with higher cystatin C values and cause eGFRcys to be lower than actual GFR.^1,5

The equation eGFRcr-cys, using both creatinine and cystatin C, typically provides the most accurate estimate of GFR for most patients in ambulatory settings.^1,3 The 2021 Medicare reimbursements were $5.12 for creatinine, $18.52 for cystatin and $10.96 for urine ACR.⁶

Application of Test Result to the Patient

For this patient, fraility, low muscle mass and inactivity are likely to have lowered the creatinine value and resulted in an eGFRcr that was substantially higher than his actual GFR. Because eGFRcys is not affected by muscle mass, it likely more accurately represents his actual GFR. However, the BMI of 37 may have increased his serum cystatin C, causing the eGFRcys to be lower than his actual GFR. Therefore, the eGFRcr-cys equation was used to guide treatment. With an eGFRcr-cys of 44 ml/min/1.73m², the patient had CKD Stage G3bA3, and his risk of progression to kidney failure within 5 years was 4.7% based on the Kidney Failure Risk Equation.⁷

What Are Alternative Diagnostic Testing Approaches?

The criterion-standard method of determining GFR is measurement of the clearance of an exogenous filtration marker, such as urinary clearance of iothalamate. A more widely available but less accurate alternative is the creatinine clearance test, which typically requires collection of urine over a 24-hour period.

Patient Outcome

For treatment of reduced kidney function and type 2 diabetes, the patient was prescribed an sodium-glucose cotransporter 2 inhibitor, empagliflozin, which was titrated to 25 mg orally daily. Over the next 11 months, his potassium ranged from 4.1 to 5.0 mEq/L and urinary ACR decreased from 504 mg/g to 195 mg/g. At 11 months after the initial presentation, his eGFRcr-cys was 40 ml/min/1.73m², and 5-year risk of progression to kidney failure of 4.7%.⁷

Clinical Bottom Line

1. eGFRcr is the initial equation recommended for estimation of GFR, although its accuracy may be affected by muscle mass, diet, frailty, advanced heart failure or liver failure, and certain medications such as trimethoprim, dronedarone, and tyrosine kinase inhibitors.

2. Serum cystatin C should be measured in adults with CKD or at risk for CKD.

3. eGFRcys may underestimate actual GFR in people who smoke cigarettes, have obesity, hypothyroidism or take systemic corticosteroids. In these individuals, eGFRcr-cys typically provides the most accurate estimate of GFR.