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Allopurinol does not work that much in CKD: a clinical trial and some possible reason beneath this failure

There are more than 1.7 million Australians with CKD and over 3,000 individuals develop kidney failure serious enough to require dialysis every year. At present, there are over 13,000 patients in Australia who are on dialysis. A major clinical trial from the University of New South Wales (UNSW) reports that a common medication called allopurinol, which is prescribed to about 20% of patients with chronic kidney disease (CKD), doesn’t work as expected. The medication in question is allopurinol, which is prescribed in patients who have gout, high uric acid due to some cancer treatments, and kidney stones composed of uric acid, to help prevent further growth of the stones. The trial was conducted by researchers from UNSW, The George Institute for Global Health, and the Australasian Kidney Trials Network.

Purines are molecules found in nucleic acid and are released from cells being broken down during digestion of food as well as during normal cell turnover in various body tissues. Hypoxanthine is a chemical generated during the metabolism of purines. Hypoxanthine is converted to xanthine via the enzyme xanthine oxidase, and then xanthine is broken down to the waste product uric acid. Allopurinol is a xanthine oxidase enzyme inhibitor. This drug is metabolized to another chemical called oxypurinol, which is similar to the natural purine breakdown product hypoxanthine. This similarity causes it to bind to and block the enzyme that converts hypoxanthine to xanthine. Since xanthine is the precursor of uric acid, this inhibition reduces the blood levels of uric acid.

Involving 31 hospitals in Australia and New Zealand, the trial lasted 2 years and examined results from 369 patients enrolled with chronic kidney disease (CKD) who were thought to be at risk of developing more severe disease. The researchers put the patients on either allopurinol or a placebo and then analyzed the rate of decline in kidney function over time. Earlier studies concluded that allopurinol treatment reduces the rate of progression of CKD. About three-fourths of people with CKD have high uric acid levels in the blood, and researchers have therefore thought that high urate levels correlate with a higher risk of CKD. However, the evidence was lacking that lowering urate levels through allopurinol delayed the progression of the disease.The current study was aimed at exploring this connection.

The researchers looked at how fast kidney function deteriorated in the group of patients on allopurinol and those without it. They found the kidney function declined at a similar rate in patients receiving allopurinol and those receiving placebo. In other words, the theory that raised blood levels of urate cause a faster deterioration of kidney function is probably not correct. Instead, they probably indicate impaired kidney function. This would mean that these patients “are likely taking medication that is of no benefit to them, unless they have other conditions that allopurinol is effective against, like gout. Allopurinol has its own side effects such as allergic reactions and skin rashes, and therefore should not be taken without evidence of benefit.

Somehow, does not wonder that allopurinol may not be that effective against CKD progression. All clinician may think that it serves to reduce uric acid; those ahving a little more extended knowledge will add that XOS inhibition may reduce the burden of oxidative stress produced by this enzyme during CKD progression. This concept is also accepted by clinical researchers in cardiology, since the employment of allopurinol for chronic heart failure (CHF) dates back at least in 2005. Given the data from basic science that higher blood uric acid predisposes to higher blood pressure and insulin-resistance, the rationale for blocking XOS pharmacologically in CKD would be beneficial meets some criteria. Hypertension and insulin-resistance are often seen in CHF or in CKD.

However, it must not be forgotten that uric acid has some physiological functions in human cells. There is some body of evidence that it behaves as a ascorbate-like molecule to scavenge some reactive oxygen (ROS) or nitrogen species (RNS). Beside, urate is not amongst the most dangerous or risky uremic toxins. Others very well known are far more biologically active, like guanidines, creatinine or indoxyl-sulphate. These have recognized lesive properties on the heart tissue, nerve cells and even bone marrow. Lately, an unbalancing activity on gut microbiota by these substances has been proven in CKD. Some scientists believe that they might worsen the kidny-gut axis during CKD progression.

However, the researchers cautioned that people already on allopurinol should not simply stop taking the drug but discuss its use with their physician. The finding is a discouraging one in some ways, as there are few effective treatments for CKD progression. Thus, there is a huge need for new treatments for this condition. This type of evidence-seeking study is crucial to improve the practice of medicine. According to Professor Sean Emory of UNSW Medicine, independent, academic research through coordinated networks is critical to changing health outcomes. He now know that a routine intervention in nephrology can no longer be justified. He thinks that linical practice will now change globally.

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

Scientific references

Badve SV et al. New Engl J Med 2020 Jun; 382:2504-2513.

Doria A et al. N Engl J Med. 2020 Jun; 382(26):2493-2503. 

Yang AY. Int J Clin Pharmacol Ther. 2020 Jan; 58(1):21-28. 

Hess S et al. Patient Prefer Adher 2019 Oct; 13:1785-90. 

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