Currently, the measurement of creatinine using Isotope Dilution Mass Spectrometry (IDMS) is standardized. Worldwide standardization of creatinine measurement has been accomplished, but selectivity issues remain due to persistence of non-selective methods leading to inaccurate creatinine and eGFR results. It is the end-responsibility of the lab professional to select and implement accurate - selective - creatinine measurement methods for adequate patient care.

In addition, it should be noted that glomerular filtration rate (GFR), defined as ml/minute passing through the kidneys as a substitute for kidney function, essentially differs from creatinine clearance which is defined as: Urinary volume * ([creatinine]_urine /[creatinine]_plasma). In case of creatinine clearance, especially with low kidney filtration, creatinine clearance may exceed GFR up to 25% due to active tubular secretion of creatinine.

Assessment of eGFR in children is outside the scope of this guideline. Specific equations for the calculation of eGFR for children and elderly may be found elsewhere (Pottel, 2016; Schwartz, 2009; Schäffner, 2012). In addition, it is not necessary to adapt the CKD-EPI formula for patients >70 years of age.

Serum or plasma creatinine is the medical test of choice for evaluating kidney function in every laboratory in the Netherlands. Due to extensive standardization efforts both at the international and the national level, the inter-laboratory variability is far below 10%. As a result of ongoing improvements in creatinine assays, methods are now available for selective measurement of creatinine with high reproducibility and small variation. As a consequence of the low analytical (total CVa <2%) and biological variability (CVw = 4-7%), creatinine measurement is currently the most suitable test for assessment of kidney function. On the basis of its high reproducibility and low variability, the serum or plasma creatinine test is suitable for detection of minimal changes during treatment (Fraser, 2011), for monitoring kidney function after kidney transplantation or after contrast medium application, and for monitoring of disease progression.

Currently no alternative test of kidney function other than creatinine is available that is reimbursed and offers high analytical reliability and low biological variation. The use of beta-trace and Cystatin C has not been validated adequately for large cohorts and these tests are not widely available in Dutch clinical chemistry laboratories.

The current use of generic and broad reference values for creatinine covers up significant changes of kidney function within the reference interval. In addition, the use of broad reference values does not permit the follow-up of vulnerable patients with slowly deteriorating kidney function. As a consequence, it is suggested that in vulnerable patients, measurement of creatinine with increased frequency leads to early detection of kidney function deterioration. Using the formula for determination of the critical difference based upon individual and analytical variability (Fraser 2011), a deterioration of kidney function can be detected with high reliability. Applying a analytical and biological variation of 2% and 5% respectively (see above), a critical difference is detected with 95% certainty (Z value 1,96, Critical difference (%) = 1,96 * √(2)* √(√(CVa) + √(CVw))) when the two consecutive measurements of creatinine differ by at least 14,9%, e.g. when a value of 100 µmol/L increases to at least 115 µmol/L or a value of 150 µmol/L increases to at least 173 µmol/L.

Following the recent validation of the CKD-EPI formula in a large cohort by Levey et al. (Levey, 2009) and by using serum creatinine standardized to the IDMS reference system, the use of the CKD-EPI equation in Dutch hospitals has been deemed feasible. The use of additional formulas, e.g. the Lund-Malmo Revised equation is not deemed usable given the specific Swedish (Caucasian) population from which this formula was derived and validated (Nyman, 2014). As per 2015, the Dutch SKML chemistry section advises the use of the creatinine based CKD-EPI formula given its improved performance for CKD risk classification compared to the MDRD formula around the clinical decision limit of 60 ml/min/1.73m².

In case the patient’s specific body surface area (BSA) is available, eGFR can be adjusted for BSA (also termed “absolute eGFR”) (Nyman, 2014).

Based upon a recent pilot study on differences in type and severity of comorbidity (Björk, 2010) and by using techniques of population weighted means, it can be estimated whether a patient has an eGFR <60 ml/min/1,73m² or ≥60 ml/min/1,73m². By stratifying patients according to their algorithms, the authors came to a preselection of patients with low or normal kidney function. In case a preselection is available of patients with increased risk for CKD or CIN follow up of these patients may be adjusted. The efficacy of these stratification studies however needs evaluation for the Dutch setting.

What is the best way to assess renal function?

Assessment of kidney function is preferable from a single measurement of an endogenous filtration marker. So far, several biomarkers have been evaluated (e.g. creatinine, Cystatin C, beta trace), although only creatinine has thus far found widespread use in most clinical chemistry laboratories. Serum creatinine measurements are the basis for creatinine-derived eGFR estimates. Historically, routine measurement of creatinine was performed using colorimetric Jaffe methods. The Jaffe method is however a chemical method affected by non-specificity since not only creatinine reacts with the alkaline picrate but also other analytes such as serum protein and glucose (Cobbaert, 2009).

The quality of the eGFR estimates is strongly dependent on serum creatinine measurement accuracy. For this reason, selective measurement of serum creatinine with analytical performance in line with desirable bias and imprecision criteria based on biological variation is paramount for guaranteeing metrological traceability. It should be kept in mind therefore that adequate risk classification using GFR critically depends on universal standardization and application of selective creatinine measurement procedures.

Following the first large study published in 1999 to estimate glomerular filtration rate (eGFR), from creatinine (Levey, 1999), the MDRD formula was further improved by using isotope dilution mass spectrometry (IDMS), (Levey, 2006) and is now subsequently replaced by the CKD-EPI equation (Levey, 2009; van den Brand, 2011). This succession of eGFR formula therefore illustrates an ongoing effort of methods to accurately estimate GFR rather than a defined endpoint. In brief, the advantage of the CKD-EPI equation, is the higher accuracy of eGFR predictions for normal kidney function than the MDRD equation. In addition, following the introduction of the CKD-EPI equation, a reduced number of patients is misclassified as compared with the MDRD equation, especially for eGFR values <60 ml/min/1.73m².

Kidney function is likely stable in patients without chronic kidney disease. Extensive risk prediction model development has indicated that underlying comorbidities such as chronic kidney disease, increased age, heart failure or impaired ejection fraction, hypotension, hypertension or shock may correlate with the possible development of AKI but are not specific for PC-AKI. The applicability of current risk models in clinical practice is only modest (Silver, 2015).

With the use of an endogenous filtration marker it should be noted that any endogenous marker is influenced by several non-GFR determinants, such as body mass, diet, racial background, gender etc. Important considerations are that eGFR is unreliable in patients with acute kidney failure and may overestimate renal function in patients with a reduced muscle mass. When adapted for specific subpopulations e.g. on the basis of descend, improvements may be possible for eGFR values, this however lies outside of the scope of this guideline.

When should an eGFR calculation be performed prior to contrast administration?

Kidney function, assessed by eGFR is, according to the working group, likely stable in patients without chronic kidney disease or, underlying comorbidities such as heart failure or, hypertension and in the absence of the use of nephrotoxic medication. In these patients, considered to have normal kidney function, an eGFR measurement should be available within approximately 12 months before any CT imaging or angiography with or without intervention with the possible use of a contrast agent. Patients who are followed-up for oncological diseases are also included in this category.

It is the opinion of the working group that an eGFR result should not be more than 3 months old in patients with CKD, a known other chronic disease or the use of nephrotoxic drugs. Chronic disease is defined in analogy to WHO criteria: chronic or non-communicable diseases are of long (more than 3 months) duration and generally slow progression. The main types are cardiovascular diseases, diabetes, chronic kidney diseases, chronic respiratory system diseases, chronic gastro-intestinal diseases, and chronic connective tissue and auto-immune diseases. (http://www.who.int/topics/noncommunicable_diseases/en/).

In patients with any acute disease or an acute deterioration of a chronic illness a recent eGFR, not more than 7 days old, is needed before CM administration. Frequently occurring examples include acute infections, acute cardiovascular diseases, acute gastro-intestinal diseases, respiratory diseases, acute kidney diseases, and acute connective tissue and auto-immune diseases. Also for all patients admitted to a hospital an eGFR <7 days old is needed before CM administration.

The nephrotoxicity of gadolinium-based contrast agents and/or microbubble contrast media and the recommendations for measurement of eGFR will be integrated with the guidelines for prevention of Nephrogenic Systemic Fibrosis. These will be published in the guideline Safe Use of Contrast Media, part 2 (due beginning of 2019).

When should an eGFR calculation be performed after the contrast administration?

There is no clear consensus guidance in the literature on this point. According to the Working Group, eGFR should be determined within 2-7 days after contrast administration in every patient with high risk for developing PC-AKI that receives preventive hydration. In patients requiring the continuation of metformin, an eGFR should be measured within 2 days. In most patients, a decreased kidney function may spontaneously resolve.

In patients without chronic kidney disease or, underlying co-morbidities such as heart failure, hypertension and not using nephrotoxic medication prior to the CM administration an eGFR determination after CM administration can be omitted.

If PC-AKI is diagnosed, how should the patient be followed-up?

In studies, eGFR was assessed after 2-3 days after CM administration to diagnose PC-AKI. In case PC-AKI is diagnosed within 2-7 days, additional follow-up is mandatory. It is the expert opinion of the Working Group that further follow-up is mandatory for patients in whom PC-AKI is diagnosed, for at least 30 days post-diagnosis with re-assessment of PC-AKI.

Emergency patients / procedures

In case of a major life-threatening medical condition requiring rapid decision-making including emergency imaging or intervention (e.g. stroke), the determination of the eGFR can be postponed or the imaging or intervention can be started while the eGFR is being determined in the laboratory. If the possibility exists to wait a short time before commencing diagnosis or intervention, without doing harm to the patient, eGFR should be determined immediately, and if indicated, individualized preventive measures should be taken before the administration of intravascular iodine-containing contrast medium.

Patient Questionnaires

In the Netherlands, for practical purposes the VMS Quality Project (VMS, 2009) has introduced to measure eGFR before every iodine-containing CM administration which has gained wide acceptance. This is not in accordance with scientific data which suggest that eGFR measurements can be performed only in patients at risk. Based on previously published risk factors (see also chapter 13 on Risk Stratification) several patient questionnaires to guide clinicians when to assess eGFR have gained popularity, especially the 6-question questionnaire (Choyke, 1998); which formed the basis for the more extensive questionnaire for multiple aspects of CM safety by the ESUR Contrast Media Safety Committee (Morcos, 2008).

For PC-AKI prevention when a contrast-enhanced examination with iodine-containing CM is planned, these questionnaires ask the patient and referring physician about: history of renal disease, history of renal surgery, and the presence of heart failure, diabetes, proteinuria, hypertension or gout. It has been shown that these simple questionnaires are sensitive in identifying patients with eGFR <45 ml/min/1.73m² and can reduce the need for eGFR assessments via laboratory or point-of-care techniques, especially in patients younger than 70 years (Azzouz, 2014; Too, 2015; Zähringer, 2015).

No literature search was performed for this chapter. The working group did not expect to find evidence for this question, since the clinical question could not be answered in a controlled study. Furthermore, the recommendations typically apply for the Dutch healthcare system.