Dietary creatine and kidney function in adult population: NHANES 2017–2018

Abstract Consuming more creatine may be associated with an increased risk of renal dysfunction, yet this link remains poorly addressed at the population level. Using 2017–2018 NHANES data, the current study found that the odds ratio for having failing kidneys in 2,955 U.S adults consuming ≥2.0 g/day of dietary creatine compared to low‐intake counterparts (<1.0 g/day) was 0.74 (95% CI from 0.39 to 1.38), indicating no significant association between dietary creatine intake and kidney dysfunction.


| INTRODUC TI ON
Creatine is a conditionally essential nutrient that is heavily involved in human energy metabolism. It serves as a spatial and temporal energy buffer for many organs with high energy needs, including the brain, skeletal muscle, kidney, and liver (Wallimann et al. 2011). A daily turnover of creatine is approximately 2.0 grams, and about half of this daily need for creatine (1.0 g/day) is obtained from the diet, while the rest is de novo synthesized inside the body. Creatine is generally considered a safe nutritional compound (Balestrino & Adriano, 2019), yet several case reports suggest that high levels of creatine in a diet may compromise kidney function (Taner et al. 2011;Thorsteinsdottir et al. 2006). In contrast, a plethora of randomized controlled studies reported no damaging effects of dietary creatine on renal function (for a detailed review see Souza et al., 2019). Still, a possible association between the risk of renal dysfunction and dietary creatine remains poorly addressed at the population level. In this cross-sectional study, the risk of kidney failure in U.S. adults consuming different amounts of dietary creatine was evaluated, using data from the 2017-2018 National Health and Nutrition Examination Survey (NHANES) round.

| ME THODS
The NHANES population includes the noninstitutionalized civilian residents of the United States. The cohort of NHANES 2017-2018 comprised a total of 9,245 male and female respondents aged 0 -80 years. For this analysis, we sorted out data for adult respondents (aged 20 years and over) who provided information on dietary intake and kidney function. Dietary intake information was obtained through dietary 24-hr recall interviews. Individual data files containing detailed information about each food/beverage item (including the description, amount of, and nutrient content) were used to calculate creatine intake from meat-based protein foods as previously described (Bakian et al. 2020). Afterward, the respondents were categorized into three groups of daily creatine intake: low-intake group (creatine intake < 1.0 g/day), medium-intake group (1.00 -1.99 g/ day), and high-intake group (≥ 2.0 g/day), with the medium-intake group excluded from the inter-group comparison. This margin was chosen due to the fact that most adults consume 1.0 gram of dietary creatine per day, which is considered a recommended amount (Brosnan et al., 2011). The information about kidney function was extracted from NHANES 2017-2018 Questionnaire Data on kidney 2258 | OSTOJIC conditions and urology codebook. Kidney dysfunction was determined for participants who positively responded to the question has he/she ever been told by a doctor or other health professional that had weak or failing kidneys (excluding kidney stones, bladder infections, or incontinence). Data collected from the NHANES 2017-2018 laboratory domain were acquired to identify relevant variables for kidney function, including blood urea nitrogen and serum creatinine, and urinary flow rate, creatinine, and albumin-to-creatine ratio.
Serum and urine samples were processed, stored, and analyzed at the

| RE SULTS AND D ISCUSS I ON
A total NHANES 2017-2018 cohort of U.S. adults who provided information on dietary intake of creatine and kidney function was 3,995 (1,930 men and 2,065 women). The mean daily intake of creatine was 0.94 ± 0.77 (95% confidence interval [CI] from 0.92 to 0.96), and 170 participants (4.26%) reported kidney failure across the whole sample. After we excluded the participants who reported medium intake of creatine, the final sample contained 2,955 respondents with either low intake (n = 2,606) or high intake (n = 349) of dietary creatine. The profiles of these two subpopulations are presented in Table 1. Except for the significantly higher dietary creatine intake found in the high-intake group (2.78 ± 0.86 g/ day versus. 0.52 ± 0.26 g/day; p <.001), no differences were found among the two groups for other variables, including kidney failure prevalence and mean values for selected biomarkers of kidney function (p >.05). In addition, the odds ratio for having failing kidneys in U.S adults consuming ≥2 g/day of dietary creatine compared to low-intake peers (<1 g/day) was 0.74 (95% CI from 0.39 to 1.38), indicating no significant association between dietary creatine intake and kidney dysfunction.
This population-level study revealed no relationship between consuming more creatine and kidney failure in U.S. adults. It appears that high-creatine consumers, who eat about 5 times more creatine per day than their low-creatine peers, show no higher risk of kidney failure. Besides, the odds ratio of 0.74 tends to favor a decreased occurrence of an event in the high-intake group, suggesting a protective outlook of consuming 2.0 grams or more creatine per day.
A case for dietary creatine-induced kidney damage has largely been built as a consequence of several case reports, including the patient with genetic mitochondrial disease (Barisic et al. 2002), an athlete who consumed 52 (!) food supplements, including creatine (Thorsteinsdottir et al. 2006), and hypertensive women supple-   the lack of additional biomarkers (e.g., plasma cystatin C, symmetric dimethylarginine, iohexol clearance) that could provide more detailed information about kidney (dys)function after an exposure (Ostojic, 2020); (c) the method of collecting dietary intake data that depends on self-reported information, instead of using independent techniques, such as the doubly labeled water or the 24-hr urine nitrogen output; (d) the omission to count for nonmeat foods and beverages as dietary sources of creatine, although those foods provide very little creatine (Hülsemann et al., 1987); and (e) setting a somewhat arbitrary threshold of low to high intake of creatine. Future populational studies should continue to monitor kidney function in the general public exposed to creatine using advanced approaches, across various age groups and dietary creatine ranges, and validate our findings that underscore no connection between kidney failure and food creatine.

S TU D I E S I N VO LV I N G H U M A N S U BJ EC TS
The study conforms to the Declaration of Helsinki for human subjects.