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Glomerular Filtration Rate Is the True Gold Standard of Kidney Function

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AKI is no longer silent

Acute kidney injury (AKI) has no obvious symptoms in the early stages, although the health care burden caused by AKI proves it is a life-threatening disease with serious long-term consequences. The complications of AKI include the need for renal replacement therapy (RRT), systemic inflammation, risk of chronic kidney disease (CKD), cardiovascular morbidity, strokes and increased mortality, in addition to an AKI-related economic burden of up to $24 billion in the U.S alone.1

This “silence” in the early stages could be related to the heavy dependence on an imperfect diagnostic standard of care (SoC), serum creatinine (SCr), to reflect kidney dysfunction in AKI. SCr is often described as a late biomarker since it starts rising only after 50% of the kidney function is already lost. In critical cases, the performance of this biomarker is also influenced by the frequently present inflammation and other non-renal factors, creating significant sensitivity drawbacks.2

Early identification of patients with AKI is one of the most critical unmet needs of physicians in their daily clinical practice. Stage 1 AKI can be stratified as two substages to improve the diagnostic accuracy of AKI by the application of biomarkers. The search for relevant kidney biomarkers has been a fervent one over the past decade. A number of claims cover the pitfalls of SCr, from earlier detection to higher sensitivity. The focus of this article is on functional kidney biomarkers since it is not possible for damage markers to estimate the glomerular filtration rate (GFR) (Figure 1).3

Figure 1: The AKI substages, GFR and biomarker value proposition.3 

The uncertainty of “today’s” eGFR

Measuring the GFR directly is considered the most accurate way to detect changes in kidney function. Historically, inulin has been considered the ideal filtration marker used to determine the “true GFR”. The classic procedure for measuring inulin clearance is rigorous and includes a continuous intravenous infusion, multiple repeat blood and urine collections, requiring experienced personnel and careful timing of blood sampling, and is typically performed only in research settings and transplant centers. Because of this, the estimated GFR (eGFR) is usually used to detect changes in kidney function.4

In clinical routine, the majority of health care providers use SCr levels to calculate eGFR. The calculated clearance of creatinine is used to provide an indicator of the eGFR, but unfortunately, the use of SCr for monitoring renal function has several limitations. SCr is not a real-time marker during the rapid change of kidney function, as its use in identifying AKI delays diagnosis even up to 72 hours.5,6,7

What are the limitations of the existing biomarker-dependent GFR formulas?

The calculation of eGFR is done through several equations incorporating multiple variables such as functional biomarker measurement (SCr in most cases), age, weight and sex. To date, several equations have been developed to calculate eGFR, and some of them are used in daily clinical practice and studies including the 2009 Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI], 2021 CKD-EPI and Modification of Diet in Renal Disease Study (MDRD).

Yet, limitations and reliability concerns for acute cases are reported on the performance of the equations such as muscle mass, nutritional state, tubular reabsorption and secretion of creatinine. It would be more accurate to attribute these shortcomings to the biomarker used and not the mathematical equation itself, since the equation performance varies with different functional biomarkers e.g., Cystatin C or with the combination of two biomarkers.8

In critically ill patients undergoing changes in muscle mass, it is extremely challenging to accurately assess kidney function using formulas depending on SCr alone. Although Cystatin C, which has a GFR estimating formula, is less likely to be influenced by non-renal determinants, it was found to be dependent on thyroid function and therapies such as glucocorticoids, limiting its use in settings such as intensive or emergency care.9

There is a need for a reliable functional kidney biomarker

PenKid is a functional kidney biomarker, measured in whole blood or plasma, that indirectly reflects the levels of the kidney stimulating hormone enkephalin, which is an endogenous opioid that stimulates kidney function.10

PenKid is validated in more than 40,000 patients and is intensively studied as a biomarker of kidney function.10 Unlike other functional kidney biomarkers, penKid is unaffected by gender, muscle mass or inflammation and shows good kinetics in both adults and children.10,11 Also, this biomarker is not only a filtration marker but directly points to the molecular pathway of renal function, which highlights its high relevance in kidney function diagnosis.

Plasma penKid concentration correlates strongly with GFR-Iohexol “true GFR” outperforming conventional measures (further details Figure 2).7 Interestingly, the elevation in plasma penKid concentration precedes the rise in SCr concentration. Therefore, penKid could help to identify critically ill patients with sub-clinical AKI, a feature that is augmented by its notable ability of kidney recovery detection.10 

Graph of plasma PENK concentrations

Figure 2: Correlation of plasma PENK concentrations with GFRiohexol (adapted from Beunders R, et al. 2020).7

Recently, an equation has been developed to estimate GFR using penKid, together with the variables creatinine and age data. This new equation had a better performance in estimating GFR compared to conventional creatinine-based equations.12

This conclusion might open the door to the possible benefits of more accurate GFR measurements. Improved management of AKI patients could be supported in the future by a penKid; delivering more timely and reliable information on kidney function.



1. Silver SA, Chertow GM. The economic consequences of acute kidney injury. Nephron. 2017; 137:297-301. doi: 10.1159/000475607

2. Shemesh O, Golbetz H, Kriss JP, Myers BD. Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int. 1985; 28:830–38. doi: 10.1038/ki.1985.205

3. The Era of AKI Biomarkers retrieved from: https://sphingotec.com/blog/the-era-of-aki-biomarkers

4. Soveri I, Berg UB, Björk J, Elinder CG, Grubb A, Mejare I, Sterner G, Bäck SE; SBU GFR Review Group. Measuring GFR: a systematic review. Am J Kidney Dis. 2014;64(3):411-24. doi: 10.1053/j.ajkd.2014.04.010.

5. Westhuyzen J, et al. Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrol Dial Transplant. 2003;18,3.543-51. doi:10.1093/ndt/18.3.543

6. Zhou H, Hewitt SM, Yuen PST, Star RA. Acute kidney injury biomarkers – needs, present status and future promise. NephSAP. 2006; 5:63–71.

7. Beunders R et al. Proenkephalin compared to conventional methods to assess kidney function in critically ill sepsis patients. Shock. 2020;54(3):308-314. doi: 10.1097/SHK.0000000000001510

8. Ebert N, Schaeffner E. New biomarkers for estimating glomerular filtration rate. J Lab Precis Med 2018;3:75. doi: 10.21037/jlpm.2018.08.07

9. Manetti L, Pardini E, Genovesi M, et al. Thyroid function differently affects serum cystatin C and creatinine concentrations. J Endocrinol Invest. 2005;28(4):346-9. doi: 10.1007/BF03347201.

10. Hollinger A et al. Proenkephalin A 119-159 (Penkid) is an early biomarker of septic acute kidney injury: The Kidney in Sepsis and Septic Shock (Kid-SSS) Study. Kidney Int Rep. 2018; 22;3(6):1424-1433. doi: 10.1016/j.ekir.2018.08.006.

11. Hartman et al.Proenkephalin as a new biomarker for pediatric acute kidney injury - reference values and performance in children under one year of age. Clin Chem Lab Med. 2020. doi: 10.1515/cclm-2020-0381.

12. Pikkers P. Using proenkephalin as a novel biomarker to estimate GFR. Retrieved from: https://sphingotec.com/webinars