Kidney function - limitations of estimated glomerular filtration rate

Fig 1: Creatinine is the most commonly used serum marker for GFR estimation. *

The glomerular filtration rate (GFR) is the volume of primary urine produced by all renal glomeruli per time unit. It is considered the best parameter to assess kidney health and function, e.g. for diagnosing different stages of chronic kidney disease (CKD). In clinical practice, GFR is usually estimated (eGFR) using the serum concentration of an endogenous filtration marker, most commonly creatinine. The requirements for an ideal GFR marker were defined by Homer Smith in 1951: It is a molecule that is freely filtered by the glomeruli into the urine without being reabsorbed or secreted (1).

Non-GFR determinants of creatinine

Although creatinine is the most commonly used serum marker to estimate GFR, its use has several limitations. In addition to glomerular filtration, its serum levels are influenced by other physiological processes such as tubular secretion or extra-renal excretion (2, 3). Tubular secretion seems to increase as GFR declines. On the other hand, secretion is inhibited by certain drugs (e.g. trimethoprim, fenofibrate and cimetidine) (3, 4). Factors affecting the extra-renal elimination of creatinine include the inhibition of gut creatininase by antibiotics and large volume losses (3). The generation of creatinine is mainly driven by skeletal muscle cells, but also influenced by diet. Endogenous creatinine production is highly dependent on muscle mass and correlates with age, sex, body size and race (5).

Creatinine is not a reliable marker for GFR in some clinical situations

False GFR estimates can be obtained in athletes or in patients who are malnourished, with severe hepatic disease or low muscle mass due to muscle wasting diseases or limb amputation (3, 4). While cooking, the creatine contained in meat is converted into creatinine, which can raise serum levels considerably. Creatinine levels can thus be influenced by a high protein diet or creatine supplements (3). GFR estimation is not reliable at non-steady state conditions of renal function as in acute kidney injury (AKI) (3). Finally, at higher GFR levels, estimates are less precise due to higher biological variability in non-GFR determinants and higher measurement error (3). Thus, creatinine can be considered a suboptimal marker in certain circumstances.

Numerous equations for GFR estimation were developed to compensate some of these limiting factors using demographic factors including age, body size and race (6). These equations such as the Chronic Kidney disease Epidemiology Collaboration (CKD-EPI) equation (7) perform reasonably well in many clinical situations, but have their limitations, e.g. in individuals with muscle mass not typical for their age and sex. In addition to the “physiological” limitations, as for every analyte, there exist analytical issues such as interference (e.g. bilirubin), imprecision and bias (3, 4).

Does accuracy matter?

Given the diverse sources of variation, the fraction of creatinine-based eGFR results within 30% of measured GFR (mGFR) ranges between 60-90% (3). In most situations, eGFR is sufficient for clinical decision making. However, there can be circumstances, where it is critical to have a very accurate measure of a patient’s GFR, because inaccurate estimates may have adverse consequences (2). As described above, creatinine-based estimates are inaccurate in persons with abnormal levels of muscle mass. This is particularly relevant for chronically ill (e.g. liver disease, malnutrition, neuromuscular disease) or hospitalized patients with reduced muscle mass. In these patients, eGFR systematically overestimates the true GFR which might lead to overdosing of medications or other medical problems. In patients with liver disease, this overestimation might delay the diagnosis of the hepatorenal syndrome or the timely start of therapies and affect decisions on simultaneous liver kidney (SLK) transplantation (8).

An accurate GFR is also important for several aspects of pharmacotherapy such as drug selection, dosing and monitoring of toxicity. As some drugs are contraindicated at low GFR, an accurate assessment of kidney function might be advisable to determine a patient’s eligibility for therapy or to select an alternative substance before administration of drugs such as platinum-based chemotherapeutics, iodine- or gadolinium-based contrast agents as well as certain antibiotics, anti-hyperglycemic or anti-hypertensive medications (9, 10). Kidney function is a major determinant for drug dosing. Overdosing drugs with a narrow therapeutic window could lead to toxicity, whereas underdosing could reduce efficacy in treatment (9, 10). Drugs can either be directly nephrotoxic or affect kidney function indirectly. Thus, monitoring for signs of toxicity is important, especially after initiation of agent, change in dose or change in symptoms (2). In the context of kidney transplantation, more accurate determination is crucial for potential living kidney donors and should be considered for monitoring of kidney transplant recipients (2).

Fig 2: Innaccurate, creatinine-based GFR estimation can be obtained in several groups of people, e.g. in patients with low muscle mass.*

Alternatives - cystatin C and mGFR

Thus, additional tests (such as cystatin C or a clearance measurement) are recommended in specific circumstances when eGFR based on serum creatinine is known to be less accurate (3).

Cystatin C is an alternative endogenous filtration marker. As with creatinine, sources of error in GFR estimation from serum cystatin C remain and include non-steady state conditions (AKI), factors affecting cystatin C generation (race, disorders of thyroid function, corticosteroid therapy) and extra-renal elimination (increased by severe decrease in GFR), measurement error at higher GFR, and interferences with the cystatin C assays (e.g. by heterophilic antibodies) (3). An equation using the combination of creatinine and cystatin C showed higher accuracy and improved the classification of CKD patients compared to an eGFR based on creatinine alone (11). The Kidney Disease: Improving Global Outcomes (KDIGO) initiative suggests measuring cystatin C in adults with eGFR (creatinine) of 45-59 ml/min/1.73 m² who do not have markers of kidney damage if confirmation of CKD is required (3).

Fig 3: Assessment of kidney function for drug dosing is important.*

Measured GFR (mGFR) can be obtained via determination of the renal (urinary) or plasma clearance of an exogenous marker. Urinary clearance requires that the patient’s urine is collected precisely over a defined time period, in some cases even via a bladder catheter. During the urine collection period, plasma is sampled. After quantitating the marker concentration in the urine and blood, mGFR is calculated as the urine concentration of the filtration marker, multiplied by the volume of the timed urine sample, and divided by the average plasma concentration during the same time period. Obtaining accurate urine collections can prove difficult, e.g. in patients with urinary incontinence or retention. This is a major reason for the rising interest in plasma clearance methods to measure GFR. The markers can usually be injected as a single bolus intravenously or subcutaneously. Measurement of the urinary clearance of inulin, an inert fructose polymer meeting all requirements for an ideal filtration marker, is considered the “gold standard” for the determination of GFR (5). However, inulin for human use is currently unavailable in the United States and measurement procedures for inulin are no longer available at most clinical laboratories (5).In addition, in most protocols, the marker needs to be continuously infused intravenously to reach steady-state. Two frequently used markers for measuring GFR are iothalamate and iohexol. An overview of GFR measurement methods and markers is given in the reviews by Stevens and Levey (2) and Seegmiller et al. (5). In summary, mGFR methods are highly elaborate and time-consuming.

There is an ongoing search for both new markers and new formulas to improve estimation of GFR in different patient populations (12). However, a single filtration marker might be unlikely to be successful because of variables other than GFR (5, 11, 12). The use of a panel of markers could improve GFR assessment by reducing errors due to variation in non-GFR determinants of each marker (13).

Novel multi-parametric test on GFR

numares developed a novel multi-parametric test based on a metabolic constellation analyzed by Magnetic Group Signaling (MGS®) empowered nuclear magnetic resonance (NMR) spectroscopy. This serum test, AXINON® Clearance Check°, combines the accuracy of renal plasma clearance methods with the convenience of creatinine-based eGFR and obviates the need for laborious and invasive tracer measurements. The metabolites used in the newly identified metabolic constellation reflect different aspects of underlying kidney pathology, such as metabolic acidosis or oxidative stress. By taking these markers into account, in addition to GFR, physicians gain a much deeper insight into kidney function. This technology is available worldwide for clinical laboratories and available on the European market as CE-marked in vitro diagnostic test. □

 Sabine Norkauer, Product Management

References

1. Smith, HW. The kidney: Structure and function in health and disease. Oxford University Press Inc, New York, 1951.

2. Stevens LA, Levey AS. Measured GFR as a confirmatory test for estimated GFR. Journal of the American Society of Nephrology : JASN. 2009;20(11):2305-13.

3. (KDOQI) KDOQI. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kindney Int. 2013;3(1).

4. Delanaye P, Cavalier E, Pottel H. Serum Creatinine: Not So Simple! Nephron. 2017;136(4):302-8.

5. Seegmiller JC, Eckfeldt JH, Lieske JC. Challenges in Measuring Glomerular Filtration Rate: A Clinical Laboratory Perspective. Adv Chronic Kidney Dis. 2018;25(1):84-92.

6. Porrini E, Ruggenenti P, Luis-Lima S, Carrara F, Jimenez A, de Vries APJ, et al. Estimated GFR: time for a critical appraisal. Nature reviews Nephrology. 2019;15(3):177-90.

7. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Annals of internal medicine. 2009;150(9):604-12.

8. Beben T, Rifkin DE. GFR Estimating Equations and Liver Disease. Adv Chronic Kidney Dis. 2015;22(5):337-42.

9. Munar MY, Singh H. Drug dosing adjustments in patients with chronic kidney disease. Am Fam Physician. 2007;75(10):1487-96.

10. Whittaker CF, Miklich MA, Patel RS, Fink JC. Medication Safety Principles and Practice in CKD. Clinical journal of the American Society of Nephrology : CJASN. 2018;13(11):1738-46.

11. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. The New England journal of medicine. 2012;367(1):20-9.

12. Steubl D, Inker LA. How best to estimate glomerular filtration rate? Novel filtration markers and their application. Current opinion in nephrology and hypertension. 2018;27(6):398-405.

13. Inker LA, Levey AS, Coresh J. Estimated Glomerular Filtration Rate From a Panel of Filtration Markers-Hope for Increased Accuracy Beyond Measured Glomerular Filtration Rate? Adv Chronic Kidney Dis. 2018;25(1):67-75.

° For Research Use only in the United States. numares’ products are not yet available for sale within the United States; they have not yet been approved or cleared by the U.S. Food and Drug Administration.

 * All photos used in this article are stock photos that were used to illustrate the contents. The depicted persons are models.