Targeting Uric Acid in CKD

In our search for therapies to reduce CKD progression, hyperuricemia has historically not been a major target despite being a potential risk factor for progression. Two recent studies however, raise the possibility that treating hyperuricemia could slow progression.

 

Should hyperuricemia be a treatment target? 

Hyperuricemia is associated with hypertension, cardiovascular disease, the metabolic syndrome, inflammation, and oxidative stress. The role of uric acid as a risk factor for incident CKD or CKD progression is more controversial. However, there are studies that suggest a pathophysiologic role for hyperuricemia. For example, in a study of over 20,000 healthy Austrians, serum levels of 7-8.9 mg/dl and ≥ 9 mg/dl were associated with odds ratios for CKD of 1.74 and 3.12 respectively. This was after adjusting for renal function, metabolic syndrome, and blood pressure agents, which are all independently associated with hyperuricemia. More recently, hyperuricemia was also associated with incident CKD in patients with type 2 diabetes. However, not all studies have shown that hyperuricemia worsens renal disease. For example, an analysis of the MDRD study, identified hyperuricemia as a risk factor for cardiovascular mortality but not renal failure.

Uric acid’s effect on inflammation, oxidative stress, and endothelial dysfunction certainly could worsen renal function. Hyperuricemia activates RAS and contributes to systemic and glomerular hypertension in animal models. Hyperuricemic animal models are associated with vascular damage and tubulointerstitial fibrosis, which can be alleviated by reducing uric acid levels pharmacologically. More information on the pathophysiology of uric acid in CKD can be reviewed here.

This year, two small studies evaluated the prospect of treating hyperuricemia to reduce CKD progression. Joel's Dream RCT coming to life.

Study 1:
Goicoechea et al published in AJKD a follow-up to their earlier trial from Spain evaluating the use of allopurinol. The original trial was a 2-year study of allopurinol, 100 mg/d, vs. placebo in 113 subjects. This recent paper described a subsequent 5-year follow-up study with 107 subjects. In their intention to treat analysis, allopurinol appeared to reduce the risk of renal events (needing dialysis or doubling of Cr) and cardiovascular events by about ½. Notably, during the follow-up period, approximately 20% of the intervention group patients stopped allopurinol while a similar percentage in the control group started allopurinol.

Study 2:
This study, again reported in AJKD performed in India, is a 6-month RCT trial of febuxostat (40 mg) vs. placebo in 93 patients. As expected, febuxostat reduced uric acid levels effectively (9 --> 5.2 mg/dL vs. 8.2 --> 7.8 mg/dL in controls). However, febuxostat also reduced the primary outcome of GFR decline with fewer patients having ≥ 10% decline in eGFR from baseline (38% vs. 54%, p 0.004).

 

So where does this leave us? 

These rather small studies, based primarily on surrogate outcomes, show that there may be a possible benefit to treating hyperuricemia, but this is far from definite. Two meta-analyses (one and two), both published prior to the recent febuxostat study, suggest that urate lowering therapy may reduce CKD progression. However, they mostly highlight the overall poor quality of evidence addressing this subject. Unfortunately, at this time there are no further trials registered on clinicaltrials.gov.

In the end, perhaps for the very concerned patient who is meeting all the other well defined goals to reduce CKD progression, hyperuricemia should be controlled to reduce CKD progression. Though clearly the data is far from conclusive.

On a related note, an international research group recently published an article about the role of uric acid damage in Mesoamerican nephropathy which is well worth reading (AJKD, “Heat stress nephropathy from exercise induced uric acid crystalluria: a perspective on Mesoamerican nephropathy”). Finally, one might wonder why humans and apes developed hyperuricemia compared to the majority of mammals. As noted here (Goh, RFN blog), hyperuricemia may have provided our ancestors with an evolutionary advantage by maintaining blood pressure in a sodium poor environment.

Robert Rope, Nephrology Fellow, Stanford

Update-  Swapnil Hiremath pointed out the ongoing CKD-FIX study (Scroll to bottom of page) in Australia and New Zealand. The group is also on Twitter- follow them @kidney_trials

"The primary aim of the study is to test the hypothesis that uric acid lowering therapy with the xanthine oxidase (XO) inhibitor, allopurinol, will significantly slow kidney failure progression in patients with moderate chronic kidney disease (CKD). 620 adult participants with CKD stages 3 or 4 who have experienced rapid progression of their CKD over the preceding 12 months will be recruited to the trial. Participants will be randomised 1:1 to receive 100-300 mg of allopurinol daily (dose dependent on CKD stage and tolerance), and treatment will be blinded to participant and treating team. The primary outcome measure will be an assessment of eGFR throughout and at the end of the 24 month treatment period as a marker of CKD progression, and a series of secondary outcomes related to blood pressure, proteinuria, cardiovascular events and death will also be measured."