Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, present >3 months, with implications for health.1 Diagnostic criteria include a decreased glomerular filtration rate (GFR) or presence of 1 or more other markers of kidney damage.1 Markers of kidney damage include a histologic abnormality, structural abnormality, history of kidney transplantation, abnormal urine sediment, tubular disorder–caused electrolyte abnormality, or an increased urinary albumin level (albuminuria).

This Test Guide discusses the use of laboratory tests that may aid in identifying CKD and monitoring and managing disease progression, comorbidities, and complications. The tests discussed include measurement and estimation of GFR as well as markers of kidney damage. A list of applicable tests is provided in the Appendix. The information is provided for informational purposes only and is not intended as medical advice. Test selection and interpretation, diagnosis, and patient management decisions should be based on the physician's education, clinical expertise, and assessment of the patient.

Estimation of GFR

Direct measurement of GFR may be problematic. The gold standard for measured GFR (mGFR) is the inulin clearance method, but this test is difficult to perform in clinical practice. Clearance measurements using iohexol, 125I-iothalamate, and several chelated isotopic radiotracers provide alternatives to the inulin reference method for mGFR, but each has limitations.2 These methods are usually reserved for specific circumstances, such as determining correct drug dosing in therapy that requires the most accurate assessment of kidney function, or when clinical decision-making is affected by having disparate results for estimated GFR (eGFR, see below).

Direct measurement of creatinine clearance and urea clearance is also an alternative to assess kidney function. Notably, the average of the 2 values is similar to GFR measured by inulin clearance (<20 mL/min/1.73 m2) in patients not on dialysis.3 In these patients, the overestimation due to creatinine secretion is offset by underestimation due to urea reabsorption, leading to an average value that accurately reflects GFR.3 However, this method of calculating GFR is prone to error due to inaccurate timing of blood sampling, incomplete urine collection over 24 hours, or over collection of urine beyond 24 hours.2,3

Given that direct measurement of GFR may be problematic, eGFR, using either creatinine- or cystatin C–based measurements, is most commonly used to diagnose CKD in clinical practice.

Creatinine-based eGFR

GFR is typically estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.4 The CKD-EPI equation uses serum-creatinine measurements, patient age (≥18 years old), and patient sex; patient race (African versus non-African ancestry) is no longer considered.4 Creatinine-based eGFR is recommended by the Kidney Disease Improving Global Outcomes (KDIGO) 2012 international guideline for initial assessment of GFR.1

Creatinine-based eGFR may be imprecise for certain individuals (see Cystatin C–based eGFR below). In addition, confirmation of GFR using another method may be required to avoid misclassification of some patients. Cystatin C–based eGFR provides an alternative when creatinine-based estimates are not appropriate.

Cystatin C–based eGFR

Being less influenced by diet and muscle mass, cystatin C–based eGFR testing is appropriate for patients in whom creatinine-based results may be misleading.5 These patients include pregnant women, patients with acute illness, patients with serious comorbid conditions, people with extremes of muscle mass (eg, bodybuilders, patients with amputation, paraplegia, muscle-wasting disease, or a neuromuscular disorder), patients suffering from malnutrition, those with a vegetarian or low-meat diet, and those taking creatine dietary supplements. In addition, the KDIGO guideline recommends using cystatin C–based eGFR, or creatinine plus cystatin C–based eGFR, to confirm CKD when creatinine-based eGFR indicates a mild to moderately high risk of CKD progression (45 to 59 mL/min/1.73 m2) in a patient without albuminuria (Figure 1).1

Figure 1. Frequency of Monitoring Chronic Kidney Disease Based on Risk of Disease Progression Assessed Using eGFR and Urine Albumin-Creatinine Ratio (Kidney Profile, test code 39165)

A large meta-analysis has shown cystatin C–based eGFR improves risk classification for adverse outcomes (death, cardiovascular disease-related death, and end-stage renal disease) across diverse populations.6 However, cystatin C–based eGFR may be more affected by some non-GFR determinants such as thyroid disorders, corticosteroid use, and smoking.2 In addition, associations of elevated cystatin C levels with diabetes, obesity, and inflammation have been reported.6,7 For these reasons, creatinine-based eGFR is recommended for patients without contraindications.

Finally, interpretation of eGFR is challenging for patients with severe obesity (BMI >40); for this group, creatinine-based eGFR may be overestimated and the utility of cystatin C–based eGFR needs to be further investigated.8

Albuminuria and proteinuria

Albuminuria indicates increased glomerular permeability, a characteristic of CKD, and is assessed with either the urine albumin-creatinine ratio or albumin excretion rate over 24 hours. The urine albumin-creatinine ratio obtained from a random sample is more convenient and appropriate in the context of CKD. However, carefully performed 24-hour specimen collection is more accurate and appropriate in some circumstances (eg, in glomerular disease when small discrepancies between the random and 24-hour results may influence high-risk therapeutic dosing).9

A urine albumin-creatinine ratio result of ≥30 mg/g (albumin excretion rate ≥30 mg/24 hours) is evidence of albuminuria (30 to 300 mg/g was formerly referred to as “microalbuminuria” and >300 mg/g as “macroalbuminuria”).1

Proteinuria (urinary total protein-creatinine ratio ≥150 mg/g) may also indicate increased glomerular permeability and CKD, but may have other causes that are distinguished by elevated nonalbumin proteins.1 Examples of other causes of proteinuria include defective tubular resorption (elevated α1- and β2-microglobulin) and tubular resorption capacity being exceeded, as observed in myeloma (elevated immunoglobulin light chains).1

GFR, albumin-creatinine ratio, and disease management

A GFR <60 mL/min/1.73 m2 for >3 months and/or urine albumin-creatinine ratio ≥30 mg/g for >3 months define CKD.1 Combined, these test results provide a “Kidney Profile” recommended by the National Kidney Foundation for diagnosing and managing CKD in at-risk patients (Figure 1).1,10-12 The results are important independent risk predictors of major adverse cardiovascular events (myocardial infarction or stroke).13

Approaches to monitoring and managing cardiovascular risk, diabetes, and other comorbidities and complications associated with the various stages of chronic kidney disease are provided in Figure 2.11

Figure 2. Testing for Comorbidities and Complications of Chronic Kidney Disease

Appendix

Quest Diagnostics offers many tests and panels for diagnosis and management of CKD. Test offerings range from health screenings for abnormal eGFR, proteinuria, and/or albuminuria, to tests for management of CKD and its comorbidities and complications. For example, the Diabetes, Advancing Chronic Kidney Disease Management Panel (test code 91713) combines many of these tests according to the recommendations of the American Diabetes Association.14

Appendix Table: Tests Used in Diagnosis and Management of Chronic Kidney Diseasea,b