Creatine Supplementation in Renal Disease
Dr Bradley Allen, FY2
A 24year old male body builder, weighing 90kg, is seen in renal outpatients as a new referral as his GP blood tests showed an eGFR of 55mls/min. He had no previous history of renal disease, nor signifcant or relevant past medical or family history. His blood pressure was 110/70mmHg, urine dipstix was clear and his creatinine was recorded as 70mmol/l. His CK was normal, as were his routine lab tests. On further questioning it becomes apparent that the patient regularly took creatine supplements as part of his weight-lifting exercise regimen, but due to a recent muscle injury the patient had not been able to train and thus had not taken any creatine supplements.
This article discusses the renal effects of creatine supplementation.
What is Creatine?
Creatine, found mostly in animals, is a non-protein amino acid that is produced in the liver, kidneys and pancreas. If ingested; mostly from meat and fish; it is absorbed by the small intestine, passes through the liver and later enters the systemic circulation. In both circumstances creatine is distributed into a myriad of tissues and once absorbed by these around 65% of creatine; in muscle and nerve cells in particular; will be phosphorylated by creatine kinase (CK) into phosphocreatine (creatine phosphate – PCr). Of note around 2% is also metabolised into creatinine (Cr) and renally excreted.
Inside our cells, the new PCr, CK and leftover creatine make up part of a complex cellular energy buffering system and to act as a buffer between sites of energy supply and consumption within the mitochondria. Put simply, phosphocreatinine is an invaluable energy store for our body and metabolism.
The enzyme CK plays a vital role in cellular metabolism and can switch between the following during periods of contrasting exercise exertion:
1. Phosphorylating Creatine by transferring a phosphate bond from adenosine triphosphate (ATP) to form PCr and ADP.
Creatine + ATP >>> Creatinine Kinase >>> Phosphocreatinine + ADP
Phosphocreatinine + ADP <<< Creatinine Kinase <<< Creatine + ATP
2. Catalysing the release of the high energy phosphate bond in PCr to adenosine disphosphate (ADP) to form ATP; notably after muscle contraction.
Phosphocreatinine + ADP >>> Creatinine Kinase >>> Creatine + ATP
Creatine + ATP >>> Creatinine Kinase >>> Phosphocreatinine + ADP
Subsequently both Creatine and PCr undergo non-enzymatic degradation into the waste product creatinine which is excreted almost solely by the kidneys. The rate of elimination of Cr is proportional to its fairly stable production and as a result, we can use it’s excretion (through plasma concentration) as a basis for renal clearance function. A raised Cr often signifies a reduction in the renal clearance of Cr and therefore by extension a decrease in renal function; however it is important to consider the possibility of a fixed excretion in the context of the raised production or ingestion of Cr / Creatine as an alternative explanation and diagnosis.
Why are Creatine supplements used?
Creatine supplements have been widely adopted in modern sport and fitness practices (Bodybuilding in particular) due to their muscle enhancing and ergonomic benefits. They are currently legal according by the World Anti Doping Agency and are not deemed to be “performance enhancing”. Despite this, current research generally supports the view that Creatine supplementation does improve performance as follows:
- Supplemented creatine aids in the resynthesis of ATP from ADP in skeletal muscle (due to the above complex creatine / PCr energy system)
- As a result, muscle contractility is improved and general recovery times shorten allowing for more intensive training to occur.
There is little research to suggest Creatine supplements have adverse side effects when taken correctly; although some case reports have highlighted potential kidney damage. Being seemed safe makes them an attractive alternative to the more infamous anabolic steroids.
Recommended dosing (Creatine monohydrate) suggests:
* Loading = 20 g / day for 5 days followed by;
* Maintenance = < 3g / day
There are two main forms of creatine supplements that are commercially available at the moment – Creatine Monohydrate (CM) and Creatine Ethyl Ester (CEE). The important differences between the two are highlighted below:
Creatine Monohydrate Creatine Ethyl Ester
Less soluble > Less absorption Better solubility in lipids > Higher absorption rates
Absorbed as CM Mostly converted to creatinine in the Gastrointestinal tract.
S.Creatine increase 1.5x* S.Creatine marginal increase*
S. Creatinine marginal increase* S.Creatinine increase x3 *
Ergogenic advantage Limited ergogenic advantage (less Creatine)
* = 6 days post ingestion
As per Spillane et al.
Why are Creatine supplements is important to consider?
As mentioned there are several reports of patients taking both sorts of creatine supplements and developing kidney damage with biopsies highlighting interstitial nephritis and acute tubular necrosis. This has however been particular felt to be a risk in patients with pre-existing renal disease or those taking higher than recommended dosing or with chronic usage. It is advised to avoid these products if there is an underlying renal pathology.
On the other hand it is important to consider the more common prospect and adversity that creatine supplementation can cause. As mentioned above research suggests that creatine supplements can lead to increases in the serum Creatinine levels. This is particularly true when taking CEE but can also occur with CM. A patient would be seen to have an elevated Cr, reduced eGFR which would not be reflective of their true renal function. These patient in some cases were investigated as having “acute renal injury” and managed as such with some having biopsies. Once supplementation is stopped their serum creatinine fell back to baseline and their “renal function normalised”; this is probable to occur within 2 weeks of cessation.
In summary it is important to remember that a raised serum creatine will not always indicate impaired renal function but can indicate increased ingestion through supplementation or through exertion. As a result, questioning patients on their drug history, lifestyle, over the counter remedies and fitness supplementations is vital.
Spillane M, Schoch R, Cooke M, Harvey T, Greenwood M, Kreider R, Willoughby DS. The effects of creatine ethyl ester supplementation combined with heavy resistance training on body composition, muscle performance, and serum and muscle creatine levels. J Int Soc Sports Nutr. 2009;6:6. doi: 10.1186/1550-2783-6-6.