In Response to Estimating Creatinine in Ultramarathon Runners by Little et al

To the Editor:

Little et al presented a valuable study concerning the accuracy of estimated creatinine in healthy runners. ¹ The authors present interesting results and analysis based on estimation of glomerular filtration rate (GFR) and the back-calculation of creatinine level. Nevertheless, although present estimation methods are widely accepted, this study exposes the limitations of this approach in the evaluation of kidney function.

There is a basic methodological problem with this estimation methodology. The excretory function of the kidney can be established on the basis of serum creatinine measurement and Modification of Diet in Renal Disease Study or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations; however, using these equations one has to assume that a patient has average muscle mass and a normal diet and that production of creatinine is stable. It is a conditio sine qua non. A low creatinine level can be a result of cachexia, and a high creatinine level is typical of bodybuilders without kidney disease.^2,3 During exercise, the production of creatinine is increased, ³ and creatinine is low in individuals on meat-free diet. ⁴ In all these situations, estimation of GFR will be misleading. The Modification of Diet in Renal Disease and CKD-EPI equations are mainly used for patients with chronic kidney diseases. In healthy populations they underestimate normal GFR. The CKD-EPI has some advantages, but it also has limitations (eg, significantly underestimating normal to high GFR levels in individuals with diabetes). ⁵

The diagnosis of acute kidney injury (AKI) is based on a relative increase in creatinine level and in some cases decrease in urine output. When serum creatinine level is changing, the GFR equation is imperfect. During exercise, when production of creatinine is increased, the creatinine level reflects not only kidney function but also muscle mass and exercise intensity. In this situation, creatinine can be measured in serum and urine to calculate creatinine clearance. Recently, we published a study showing that creatinine clearance remained unchanged after ultramarathon, although serum creatinine was significantly increased. ⁶ Another method to diagnose early AKI is based on cystatin C (CysC) measurement. ³ CysC has been recognized as a promising marker of GFR, and controlled physiological studies have demonstrated that acute changes in CysC provide a better approximation of GFR than serum creatinine. ⁷

It can be difficult to diagnose early kidney injury; as a result, some new markers of AKI, such as neutrophil gelatinase lipocalin (NGAL) and kidney injury molecule-1, have been proposed. Although not widely used in clinical practice, these markers were tested in experimental studies. Urinary NGAL was increased after long endurance exercises, ⁸ whereas after short, intense exercise (treadmill test) urinary NGAL remained unchanged and urinary kidney injury molecule-1 was significantly increased. ⁹ The significance of recurrent postexercise increases in creatinine and new markers of AKI has not been established. The increase in creatinine level can be a sign of severe dehydration (prerenal azotemia), which is a benign condition, but it is possible that recurrent episodes of dehydration and muscle injury may contribute to subsequent kidney function. ¹⁰

In summary, the authors presented a very interesting study and showed that some calculations used in clinical practice should not be used for the evaluation of kidney function in healthy runners.