The Role of Allopurinol in Chronic Kidney Disease?

 

 Following an article “ Understanding Gout: A Multifaceted Condition” I penned today in the link below for Christmas, Professor Dr Vythilingam, a medical doctor friend of mine,  posed this question for me:

“Thank you very much Prof. This will be a good read for Christmas. I would like to request another article in your blog on the role of allopurinol medication in CKD with non-gout uricemia. I would appreciate that very much Sir. Thank you and have a wonderful day with family and friends”

 
https://scientificlogic.blogspot.com/2024/12/understanding-gout-multifaceted.html

 

First, I thank Professor Vythi, a vegan, for his very challenging Christmas question for me to field. Now I need to write, not one, but two Christmas articles today for Xmas. I don’t think I will be able to have a wonderful day with family and friends for Christmas having to deal with two articles today. Anyway, I like academic challenges come what may even if I need to cross hostile territories with gun fires at my defenceless self.   

 

Understanding the Mode of Action of Allopurinol:

 

First of all, before I answer Professor Vythi, let me explain the pharmacodynamic how allopurinol works. Allopurinol is a purine analogue that has been first line treatment for gout since the 1960s As far as my knowledge on medicine and pharmacology allows me, when allopurinol is given to a patient with elevated uric acid (uricemia or even hyperuricemia),  it is metabolized in the liver to its active metabolite, oxypurinol (alloxanthine) via endogenous pathways that normally function for the purines, hypoxanthine and xanthine.

 In the human liver this reaction is primarily carried out by aldehyde oxidase (AOX1).  Allopurinol and its active metabolite inhibit xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid.

In short, allopurinol is used in the management of elevated uric acid that causes gout. However, Professor Dr Vythilingam asked me the role of allopurinol in CKD (chronic kidney disease) with no gout uricemia?

Let me try to handle this very challenging question because in CKD, it is not just hyperuricemia but uraemia, a general buildup of all waste products that normally can only be treated with haemodialysis

To answer the specific question regarding its role in chronic kidney disease without gout or uricemia, let me try to explain  this  topic systematically.

The use of allopurinol in CKD patients who do not have gout-related hyperuricemia has been a subject of investigation. While uraemia in CKD involves the accumulation of various toxins due to impaired renal clearance, uric acid plays a unique and potentially harmful role, even in the absence of gout symptoms.

Firstly, we need to examine the role of uric acid in CKD progression. Although not all CKD patients have hyperuricemia, elevated uric acid levels—even within the "high-normal range"—may contribute to:

First, on renal vascular dysfunction.  Uric acid promotes endothelial dysfunction, oxidative stress, and inflammation, worsening renal perfusion.

Second, on renal interstitial damage.  Uric acid crystals or related inflammatory responses can damage tubular cells, accelerating kidney damage.

Third, hypertension and cardiovascular complications.  Uric acid may activate the renin-angiotensin-aldosterone system (RAAS), contributing to high blood pressure and cardiovascular strain.

For these reasons, uric acid is considered a modifiable factor in CKD progression.

Our question is, what would be allopurinol’s potential benefits in CKD?

The first answer I can give is, the  reduction of oxidative stress and inflammation. By this, I mean by inhibiting xanthine oxidase, allopurinol reduces the production of reactive oxygen species (ROS), which are generated during uric acid formation. This mitigates oxidative damage in CKD.

My second answer is, the  slowing of CKD progression.  Some studies (e.g., the CKD-FIX trial and earlier observational studies) suggest that allopurinol might slow the decline in glomerular filtration rate (GFR) by reducing uric acid-associated damage, even in patients with normal serum uric acid levels.

My Third answer is, there may be an improvement in cardiovascular outcomes since CKD patients are at high risk of cardiovascular complications, reducing oxidative stress and endothelial dysfunction with allopurinol may offer additional benefits.

There is clinical evidence supporting my answers using allopurinol in CKD. For example, studies by Goicoechea et al., in 2010 have shown positive outcomes where a randomized controlled trial showed that CKD patients treated with allopurinol had slower GFR decline and fewer cardiovascular events than controls, even when uric acid levels were not markedly elevated. Furthermore, there was a reduction in proteinuria.  Allopurinol has been associated with reduced proteinuria, a marker of kidney damage.

However, there are also studies with mixed results. For example, in the CKD-FIX trial (2020), a larger and more rigorous study, found no significant difference in GFR decline between allopurinol and placebo in CKD patients. However, allopurinol was well-tolerated, and secondary benefits (e.g., cardiovascular effects) were not fully explored.

Nevertheless, I need to provide caution with allopurinol in CKD.

First, dosage adjustment is required. Allopurinol and its metabolite, oxypurinol, are excreted renally, so dosing must be adjusted to avoid accumulation and toxicity in CKD patients.

Then we need to look at the risk of hypersensitivity reactions.  Patients with advanced CKD are at higher risk of allopurinol hypersensitivity syndrome (AHS), a rare but severe reaction.

But all is not lost. There is an alternative to allopurinol, and that is - Febuxostat

In patients with CKD, febuxostat, a non-purine xanthine oxidase inhibitor, may be an alternative. It is primarily metabolized in the liver and less dependent on renal excretion, potentially reducing toxicity in CKD patients. However, its cardiovascular safety profile remains a concern.

My concluding  answer to Professor Vythi's very difficult question is,  the role of allopurinol in CKD without gout-related hyperuricemia lies in its potential to slow CKD progression and reduce oxidative stress and inflammation. However, the evidence is mixed, and its routine use in this context is not yet universally endorsed. Clinical judgment, careful patient selection, and close monitoring are essential, especially considering the risk of toxicity in advanced CKD.

Allopurinol might be beneficial in specific CKD patients with borderline uric acid levels, inflammation, or high cardiovascular risk, but it is not a substitute for haemodialysis in managing uraemia. Its use should be considered as part of a multifactorial approach to managing CKD.

I hope my explanation provides clarity and satisfies your curiosity Professor. Wishing you a joyful and peaceful 2024 Christmas Professor Dr Vythilingam.

No more questions  from anyone for now as I have been searching for the literature and have been typing out my answers all day through this “blessed” Christmas Day since Christmas Eve last evening .

I need dinner now to survive.

Warm regards,

ju-boo lim

8:38 pm Malaysian Time

25 December 2024.