Creatine is a Conditionally Essential Nutrient in Chronic Kidney Disease: A Hypothesis and Narrative Literature Review

To accommodate the loss of the plethora of functions of the kidneys, patients with chronic kidney disease require many dietary adjustments, including restrictions on the intake of protein, phosphorus, sodium and potassium. Plant-based foods are increasingly recommended as these foods contain smaller amounts of saturated fatty acids, protein and absorbable phosphorus than meat, generate less acid and are rich in fibers, polyunsaturated fatty acids, magnesium and potassium. Unfortunately, these dietary recommendations cannot prevent the occurrence of many symptoms, which typically include fatigue, impaired cognition, myalgia, muscle weakness, and muscle wasting. One threat coming with the recommendation of low-protein diets in patients with non-dialysis-dependent chronic kidney disease (CKD) and with high-protein diets in patients with dialysis-dependent CKD, particularly with current recommendations towards proteins coming from plant-based sources, is that of creatine deficiency. Creatine is an essential contributor in cellular energy homeostasis, yet on a daily basis 1.6-1.7% of the total creatine pool is degraded. As the average omnivorous diet cannot fully compensate for these losses, the endogenous synthesis of creatine is required for continuous replenishment. Endogenous creatine synthesis involves two enzymatic steps, of which the first step is a metabolic function of the kidney facilitated by the enzyme arginine:glycine amidinotransferase (AGAT). Recent findings strongly suggest that the capacity of renal AGAT, and thus endogenous creatine production, progressively decreases with the increasing degree of CKD, to become absent or virtually absent in dialysis patients. We hypothesize that with increasing degree of CKD, creatine coming from meat and dairy in food increasingly becomes an essential nutrient. This phenomenon will likely be present in patients with CKD stages 3, 4 and 5, but will likely be most pronouncedly present in patients with dialysis-dependent CKD, because of the combination of lowest endogenous production of creatine and unopposed losses of creatine into the dialysate. It is likely that these increased demands for dietary creatine are not sufficiently met. The result of which, may be a creatine deficiency with important contributions to the sarcopenia, fatigue, impaired quality of life, impaired cognition, and premature mortality seen in CKD.