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Uric acid and mortality: is really necessary to cut urate down when it is higher?

Extreme values of serum uric acid levels in the blood can markedly reduce a patient’s chance of surviving and reduce their lifespans by up to 11 years, according to a new study by researchers at University of Limerick’s School of Medicine. In one of the largest studies and the first of its kind in Ireland, researchers found evidence of substantial reductions in patient survival associated with extreme concentrations of serum uric acid (SUA) for both men and women. Dr Leonard Browne, PhD, Senior Research Fellow in Biostatistics, UL School of Medicine is the lead author of the research. The study, which was seed-funded by the Health Research Board (HRB), has just been published in the European Journal of Internal Medicine. This is the first study to yield detailed survival statistics for SUA concentrations among Irish men and women in the health system. The key question of the team was to determine whether SUA, a routinely measured blood marker, could help clinicians predict a patient’s lifespan, all else being equal.

To answer this, the research team used data from the National Kidney Disease Surveillance System (NKDSS), based at UL, and created a large cohort of 26,525 patients who entered the Irish health system at University Hospital Limerick between January 2006 and December 2012, following them until December 2013. The results were quite astonishing because for men the message was quite clear. The median survival was reduced by an average of 9.5 years for men with low levels of SUA (less than 238μmol/L), and 11.7 years for men with elevated SUA levels (greater than 535 μmol/L) compared to patients with levels of 357-416 μmol/L. Similarly, for women, the researchers found that the median survival was reduced by almost 6 years for those with SUA levels greater than 416 μmol/L, compared to women with SUA in the normal range. Therefore, the shape of the mortality curves was quite different for men and women.

For men the shape of the association was predominantly U-shaped with optimal survival between 304-454 μmol/L, whereas, for women, the pattern of association was J-shaped with elevated risk of mortality only present for women with SUA levels beyond 409 μmol/L. According to the current scientific knowledge, there is good evidence that high levels of SUA are associated with a range of serious chronic medical conditions such as kidney failure, hypertension, heart disease, stroke and diabetes. The team thinks that these known associations might in part explain the high mortality observed for patients with elevated SUA levels in their study. Indeed, when they looked at the cause of death for these patients they found on one hand that men and women with very high uric acid levels died from cardiovascular causes of death. On the other hand, and quitesurprisingly, they also found that very low levels of SUA were also associated with a higher risk of death primarily in men.

This would of course suggest that very low levels of uric acid are also detrimental to survival. Uric acid is a by-product of the nucleotide bases metabolism and is popularly and historically associated with gout. However, last decades biochemical studies proved that it is also linked with conditions like heart disease, high blood pressure, stroke and kidney failure. Biochemical aspects of these actions are known: elevated SUA is associated usually with oxidative stress and free oxidant species (like peroxide, superoxide or nitric oxide) may modify uric acid into byproducts that may cause direct cytotoxicity. On the other side, low levels of uric acids may predispose to shorter lifespan as well as reported by the research. Also this aspect is potentially connected to oxidative stress. At regular serum levels, uric acid has vitamin C-like scavenging abilities and may quench reactive species like hydrogen peroxide and peroxynitrite, which are known to damage blood vessels.

Interestingly, the team noted that men who died with low SUA levels had a higher proportion of deaths from cancer – unlike those with high SUA level who had a higher proportion of deaths from cardiovascular disease. Previous work by the research group found that hyperuricemia is very common and affects about 25% of adults in the health system with a pattern of increasing growth year-on-year. This current study adds to the body of evidence on the importance of SUA as a major predictor of survival and a potential target for treatment. Professor Stack, senior author and head of NKDSS, commented that a key consideration is whether clinicians should treat hyperuricemia and lower SUA levels to a desired target level in order to extend patient survival. Prospective clinical trials are currently underway using uric acid lowering drugs in order to provide a definitive answer to this question. This will help shape treatments for people with conditions like heart disease, stroke and kidney disease.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Browne LD et al. Eur J Internal Med 2020 Oct 19.

Rohn B et al. Ren Fail. 2020 Nov; 42(1):1067-75. 

Yoshida H et al. Ren Fail. 2020 Nov; 42(1):646-55. 

Kodama S et al. Cardiovasc Drugs Ther 2020 Oct 23. 

Lee CL, Tsai SF. Sci Rep. 2020 Oct 16; 10(1):17585. 

Dott. Gianfrancesco Cormaci
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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