Wyss & Kaddurah-Daouk 2000: Creatine and Creatinine Metabolism — Study Summary

Creatine.my Editorial Team · · 5 min read
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5 min read
This content is for educational purposes only and is not medical advice. Consult a healthcare provider before starting any supplementation.

Study Overview

Wyss and Kaddurah-Daouk (2000) published a landmark comprehensive review in Physiological Reviews covering the complete biochemistry, physiology, and pathology of the creatine-creatinine system. This 90-page review remains one of the most thorough treatments of creatine metabolism in the scientific literature, covering endogenous synthesis, dietary intake, cellular transport, the creatine kinase reaction, creatinine formation, and the relevance of this system to various diseases (T et al., 2011) .

1-2g
of creatine synthesised endogenously per day by the kidneys and liver — supplementation adds to this baseline production
Wyss & Kaddurah-Daouk, 2000

Key Findings

  • Two-organ synthesis: Creatine synthesis requires cooperation between the kidneys (which produce the precursor guanidinoacetate via AGAT) and the liver (which converts guanidinoacetate to creatine via GAMT). This two-organ system uses approximately 40% of all S-adenosylmethionine (SAM) produced by the body
  • Creatine transporter is essential: The SLC6A8 creatine transporter is required for cellular creatine uptake. Mutations in this transporter cause creatine deficiency syndromes with severe neurological consequences, underscoring creatine’s importance for brain function
  • Creatinine is an irreversible endpoint: The conversion of creatine to creatinine is non-enzymatic, irreversible, and occurs at a constant rate (~1.7%/day). This continuous loss means the body must constantly replenish creatine through synthesis and diet
  • Creatine kinase system is multifunctional: Beyond simple energy buffering, the creatine kinase system serves as an energy shuttle, pH buffer, and metabolic signal integrator across cells
  • Disease relevance: Disruptions in creatine metabolism are implicated in numerous conditions including inborn errors of creatine synthesis, neurodegenerative diseases, and muscle wasting disorders

Practical Implications

This comprehensive review provides the biochemical foundation for understanding why creatine supplementation works and why it is needed. The key practical insight is that the body loses approximately 2g of creatine daily through irreversible creatinine conversion. This must be replaced through a combination of endogenous synthesis (~1-2g/day) and dietary intake (~1-2g/day from meat and fish).

For Malaysian vegetarians or those with low meat intake, dietary creatine may be insufficient to fully replenish daily losses, making supplementation particularly valuable. The 3-5g/day recommendation provides a comfortable surplus above daily losses, ensuring muscle creatine stores remain at or near saturation.

The clinical implication of elevated creatinine from supplementation is important for Malaysian healthcare: doctors should be aware that patients taking creatine will show elevated serum creatinine that does not indicate kidney disease. This is particularly relevant in Malaysia’s public healthcare system where routine blood tests may flag elevated creatinine (RB et al., 2017) .

Study Limitations

  • As a comprehensive review rather than original research, it synthesises rather than generates new data
  • Some areas discussed were still poorly understood at the time of publication and have since been updated
  • The review predates many of the clinical trials on creatine supplementation in special populations
  • Some of the disease associations discussed were speculative and have not been fully confirmed by subsequent research
  • The focus on biochemistry means practical supplementation recommendations are limited

Study Design and Methodology

Understanding how a study was designed helps assess the strength of its conclusions. Key methodological factors to evaluate include:

  • Sample size — larger studies (n=50+) provide more reliable results than small studies (n=10-15). Small sample sizes increase the risk of false positives and limit the ability to detect moderate effect sizes
  • Study duration — creatine research requires adequate duration for muscle saturation (minimum 4 weeks for maintenance dosing, 1 week for loading). Studies shorter than this may miss the full effect
  • Blinding — double-blind, placebo-controlled designs (where neither researchers nor participants know who receives creatine) are the gold standard for minimising bias
  • Population studied — results from trained athletes may not fully apply to untrained individuals, and vice versa. Age, sex, and dietary habits (particularly vegetarian status) also influence creatine response
  • Outcome measures — direct measures (muscle biopsy, MRS imaging) are more informative than indirect proxies (blood markers, performance tests) for assessing creatine uptake and metabolism

Clinical Implications and Practical Relevance

This research contributes to our understanding of creatine in several practical ways:

For athletes and fitness enthusiasts: The findings support the use of creatine monohydrate as a safe, effective ergogenic aid. The standard dosing protocol of 3-5g daily remains well-supported by the cumulative evidence base including this study.

For healthcare professionals: Understanding the specific mechanisms and safety data from studies like this helps clinicians provide evidence-based guidance to patients who ask about creatine supplementation. The research consistently shows a favourable safety profile at recommended doses.

For the Malaysian context: While most creatine research is conducted in Western populations, the fundamental biochemistry (ATP-phosphocreatine system) is universal. Malaysian consumers can apply these findings with confidence, adjusting for local factors like tropical climate (increased hydration needs) and halal dietary requirements (synthetic creatine monohydrate is permissible).

How This Fits Into the Broader Evidence

No single study should be used to make definitive claims about creatine supplementation. Instead, this research should be viewed as one piece of a much larger evidence base:

For a complete overview of the evidence, explore our Research Library which covers 60+ landmark creatine studies.

Sources & References

This page summarises Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiological Reviews. 2000;80(3):1107-1213.

Further Reading

Frequently Asked Questions

Where is creatine made in the body?

Wyss & Kaddurah-Daouk (2000) detailed that creatine is synthesised in a two-step process. First, the enzyme AGAT in the kidneys produces guanidinoacetate (GAA) from arginine and glycine. Then, the enzyme GAMT in the liver methylates GAA using S-adenosylmethionine (SAM) to produce creatine. This endogenous synthesis produces approximately 1-2g of creatine per day.

What is the relationship between creatine and creatinine?

Creatinine is the spontaneous degradation product of creatine and phosphocreatine. Approximately 1.7% of the total creatine pool is converted to creatinine daily through a non-enzymatic, irreversible reaction. Creatinine is then filtered by the kidneys and excreted in urine. This is why creatinine levels are used as a marker of kidney function.

Does creatine supplementation affect creatinine blood test results?

Yes. Creatine supplementation increases total body creatine stores, which proportionally increases creatinine production. This can elevate serum creatinine levels and may be misinterpreted as impaired kidney function. It is important to inform your doctor that you take creatine so that elevated creatinine levels are interpreted correctly.