Functional Age BioMarkers Part 6: Creatinine

Welcome to part 6 of ODX's "Functional Age Biomarkers" Series. In the sixth post, you'll learn why increasing creatinine is associated with increasing biological age, which, in turn, is associated with cognitive decline, a potential indicator of early mortality.

The ODX Functional Age Biomarkers Series

Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN

1. Functional Age Biomarkers Part 1: Introduction and Overview
2. Functional Age Biomarkers Part 2: Fasting Glucose
3. Functional Age BioMarkers Part 3: C-Reactive Protein (CRP)
4. Functional Age Biomarkers Part 4: Albumin
5. Functional Age BioMarkers Part 5: Alkaline Phosphatase
6. Functional Age BioMarkers Part 6: Creatinine
7. Functional Age BioMarkers Part 7: Red Cell Distribution Width (RDW)
8. Functional Age BioMarkers Part 8: Mean corpuscular volume (MCV)
9. Functional Age BioMarkers Part 9: Lymphocytes
10. Functional Age BioMarkers Part 10: WBCs

Creatinine reflects kidney function, muscle metabolism

Physiological changes associated with elevated creatinine

The kidneys are responsible for removing metabolic waste products, drug metabolites, xenobiotics, and other toxins; regulating blood pressure; regulating blood levels of vital compounds, including glucose, sodium, potassium, and phosphate; and secreting hormones, including renin. erythropoietin, and calcitriol (active vitamin D). Risk factors that can contribute to kidney damage include oxidative stress, CVD, diabetes, hypertension, smoking, and excess red meat intake. Notable changes in the physiology and structure of the kidney are observed with the aging process. Renal parenchyma volume decreases, adipose tissue accumulates in the renal sinuses, glomerular basement membranes thicken, nephrosclerosis progresses, and mesangial widening and accumulation of extracellular matrix increase. Creatinine increases as the kidney's ability to filter decreases. This filtering ability is reflected in the estimated glomerular filtration rate (eGFR). The eGFR is expected to decline by 0.4-2.6 mL/min/year. An eGFR below 60 mL/min/1.73 m2 is associated with chronic kidney disease. A decline in glomerular filtration rate is also associated with obesity, doubling CKD risk (Dybiec 2022). A doubling of serum creatinine likely represents a 50% reduction in glomerular filtration rate (Pagana 2022).

Chronic kidney disease promotes vascular damage, oxidative stress, systemic inflammation, and uremic toxicity, factors that may be directly involved in brain lesion development and cognitive decline (Xie 2022). Declining kidney function is also associated with declining visual memory, verbal memory, and learning (Seliger 2015). Creatinine is highly correlated with homocysteine, a metabolic waste product that may reflect compromised kidney function (Elias 2009).

Creatinine and cognitive decline

Declining kidney function is associated with declining cognitive function, and a decreased eGFR may be an independent indicator of cognitive dysfunction. Kidney and cognitive dysfunction were associated in TILDA, a large cohort study of 8,175 healthy individuals over 50. Researchers note that kidney dysfunction and cerebrovascular disease share common pathological pathways involving NT-proBNP and GDF15 (Nowak 2023).

Chronic kidney disease reflects accelerated vascular brain aging, and a lower eGFR is associated with brain atrophy. A strong relationship is seen between declining kidney function and declining cognitive function once eGFR drops below 45 mL/min/1.73 m2, with more moderate-to-severe cognitive impairment occurring when eGFR falls below 30. Cognitive impairment is independently associated with a urinary albumin to creatinine ratio above 30 mg/g. The UACR reflects kidney function and is also a measure of vascular endothelial inflammation and brain atrophy. Research also finds that cortical thinning, a measure of brain atrophy, was associated with an eGFR of 31-60 min/mL/1.73m2 versus an eGFR above 83 (Murray 2023).

Creatinine and biological age

Increasing creatinine is associated with increasing biological age which, in turn, is associated with cognitive decline, a potential indicator of early mortality (Erema 2022). Renal function is considered an essential predictor of longevity and early identification of renal dysfunction is critical. The kidney is one of the organs most susceptible to aging and a linear decline in function can be seen in healthy adults after age 30 (Dybiec 2022).

Creatinine is significantly associated with mortality and chronological age and can be used to assess biological age (Erema 2022).. An eGFR of 90 mL/min/1.73 m2 or above is normal and considered “stage 1,” 60-89 stage 2, 30-59 stage 3, 15-29 stage 2, and below 15 mL/min/1.73 m2 is stage 5, representing a very high risk of CKD. For stages 2-5, biological age is increased by 3-9 years, respectively (Abu 2022).

Chronic kidney disease is associated with increased morbidity and mortality and is considered the main warning sign of premature aging. It is closely associated with cardiovascular disease and GFR is inversely proportional to cardiovascular mortality worldwide (Figuer 2021). Exercise and a healthy diet, including sources of resveratrol, can help support renal function and healthy aging (Dybiec 2022).

References

Abu Bakar, Shaiful Anuar et al. “Biological age for chronic kidney disease patients using index model.” PeerJ vol. 10 e13694. 1 Aug. 2022, doi:10.7717/peerj.13694

Dybiec, J., et al. "Structural and Functional Changes in Aging Kidneys." *Int J Mol Sci.*, vol. 23, no. 23, 2022, doi:10.3390/ijms232315435.

Elias, Merrill F et al. “Chronic kidney disease, creatinine and cognitive functioning.” Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association vol. 24,8 (2009): 2446-52. doi:10.1093/ndt/gfp107

Erema, V. V., et al. "Biological Age Predictors: The Status Quo and Future Trends." *Int J Mol Sci.*, vol. 23, no. 23, 2022, doi:10.3390/ijms232315103

Figuer, Andrea et al. “Premature Aging in Chronic Kidney Disease: The Outcome of Persistent Inflammation beyond the Bounds.” International journal of environmental research and public health vol. 18,15 8044. 29 Jul. 2021, doi:10.3390/ijerph18158044

Kashani, Kianoush et al. “Creatinine: From physiology to clinical application.” European journal of internal medicine vol. 72 (2020): 9-14. doi:10.1016/j.ejim.2019.10.025

Murray, Anne M, and Prashanthi Vemuri. “Kidney Disease and Brain Health: Current Knowledge and Next Steps.” American journal of kidney diseases : the official journal of the National Kidney Foundation vol. 81,3 (2023): 253-255. doi:10.1053/j.ajkd.2022.09.007

Nowak, Natalia et al. “The association between kidney function, cognitive function, and structural brain abnormalities in community-dwelling individuals aged 50+ is mediated by age and biomarkers of cardiovascular disease.” Cardiovascular research vol. 119,11 (2023): 2106-2116. doi:10.1093/cvr/cvad060

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 16th ed., Mosby, 2022.

Seliger, Stephen L et al. “Renal function and long-term decline in cognitive function: the Baltimore Longitudinal Study of Aging.” American journal of nephrology vol. 41,4-5 (2015): 305-12. doi:10.1159/000430922

Shahbaz, Hassan. and Mohit Gupta. “Creatinine Clearance.” StatPearls, StatPearls Publishing, 25 July 2022.

Xie, Zuoquan et al. “Chronic Kidney Disease and Cognitive Impairment: The Kidney-Brain Axis.” Kidney diseases (Basel, Switzerland) vol. 8,4 275-285. 3 May. 2022, doi:10.1159/000524475