Uric Acid and Progression of Kidney Disease

Marian Goicoechea

Dr. Marian Goicoechea

New data over the last decade have forced us to relook at the possibility of a causal relationship between high uric acid levels and chronic kidney disease (CKD). A steady stream of epidemiologic data has shown that elevated serum uric acid level is an independent risk factor for incident kidney disease in the general population (see here as well). The next question is, “Should we treat high uric acid level in an asymptomatic CKD patient, or even in a perfectly normal patient?

In an attempt to answer this question, a randomized study from 2010 showed that treatment of high uric acid with allopurinol could prevent a decline in GFR in patients with CKD over two years of follow-up. And now, the recently published results of a post hoc analysis from Goicoechea et al confirm that long term treatment with allopurinol not only slows progression of CKD, but also reduces cardiovascular risk. This conclusion is based on a seven-year follow-up period. Could this be compelling evidence for uric acid lowering therapy to be considered a standard intervention for slowing CKD progression? Does this data suggest at-risk patients should be treated to prevent incident CKD? Corresponding author Dr Marian Goicoechea (MG) discussed this study with Dr. Veeraish Chauhan (eAJKD), eAJKD Contributor.

eAJKD: Do you think asymptomatic hyperuricemia merits treatment in CKD patients?

MG: Numerous epidemiologic studies have shown an association between hyperuricemia and the risk of kidney disease. Although this finding is not universal, we think there is sufficient epidemiologic data to try to establish a causal relationship between hyperuricemia and progression of kidney disease. Currently, there are some small published studies showing that lowering uric acid prevents progression of CKD.  While our long-term follow up study reinforce these data, larger, multicenter, and randomized studies are needed to confirm these findings.

eAJKD: There is literature to support using allopurinol to reduce CV and kidney outcomes in CKD patients. How is your analysis different?

MG: Our study is the first to confirm that long-term treatment with allopurinol slows the progression of chronic kidney disease and prevents the entry on dialysis. Until now all the published studies have short follow up.  This study extends the follow up to 7 years. Furthermore, it is the first study that uses hard end-points, such as entering dialysis or doubling of serum creatinine. In relation to cardiovascular risk, our study also shows that treatment with allopurinol reduces long-term cardiovascular risk.

eAJKD: Could you summarize the results for our readers?

MG: In the original study, 113 participants with CKD stage 3 and 4 (57 in the allopurinol group and 56 in the control group) were followed for 2 years.  In the long-term follow up reported in this article, 107 participants were followed up to 5 additional years (56 in the allopurinol group and 51 in the control group). After a median follow-up of 7 years, allopurinol was shown to reduce the risk of kidney events (initiating dialysis therapy and/or doubling serum creatinine level and/or ≥ decrease in GFR) by 68% and the risk of cardiovascular events by 57%.

eAJKD: What target uric acid level should a practicing nephrologist aim for as part of routine CKD-patient care?

MG: This is a difficult question to answer, since epidemiologic studies show associations with different cutoffs of uric acid and renal disease progression.  Furthermore, there are few studies designed to show that the lowering uric acid levels will lower cardiovascular or renal risk. Until these questions are resolved, we believe it is advisable to keep uric acid levels below 7 mg/dL, but this is an opinion not supported by any evidence grade.

eAJKD: Any thoughts on role of febuxostat versus allopurinol on lowering uric acid levels?

MG: To date, we do not have any clinical trial with febuxostat showing its beneficial effect on cardiovascular or renal risk. Theoretically, febuxostat is a selective inhibitor of xanthine oxidase, and is more potent than allopurinol in reducing uric acid. These advantages could help reduce cardiovascular and renal risk, but comparative studies are needed to confirm this hypothesis.

eAJKD: Can you suggest specific changes in clinical nephrology practice?

MG: We think that our results are important enough to support the option of treating asymptomatic hyperuricemia in patients with CKD stage 3 and 4.  We are similarly aware of the limitations of our study: small sample size, no double-blind, single-center study, and post hoc follow-up analysis.

To view the article abstract or full-text (subscription required), please visit AJKD.org.

 

5 Comments on Uric Acid and Progression of Kidney Disease

  1. N Gopalakrishnan // February 11, 2015 at 1:38 pm // Reply

    Certainly, a clinical paradigm. Yet another interventional tool to retard CKD progression.
    But, allopurinol, by itself is also a free radical scavenger. How to be certain that it’s benefit in reducing CV event risk is due to reduction of uric acid levels alone.

    • Thanks for your comment, I’m sorry but it is a question that at present can not be answered. Indeed, xanthine oxidase blockers reduce oxidative stress, and this effect may be responsible for reducing cardiovascular risk. This question should be answered with a designed study that comparing the effect of xanthine oxidase blockers versus uricosuric drugs in the cardiovascular risk reduction.

  2. I agree with Dr. Gopalakrishnan, that Uric acid is a MARKER and NOT A ‘TRUE’ risk factor at present, and using XO inhibitors to lower uric acid, decrease the production of Per-Oxynitrite, thereby suggesting reducing uric acid is helpful in retardation of progression of CKD or reducing CV risk, and agree with Dr. Goicoechea, that until a well designed study, comparing the XO inhibitors (that will reduce both uric acid and peroxynitrite) to Uricosuric drugs (that reduce uric acid but not peroxynitrite) are done, one should claim uric acid to be a MARKER, than a “TRUE” Risk Factor.

  3. maybe allopurinol is not the medicine to lowering uric acid, but this medicine is cheap and effective enough.

  4. ERNEST KIOKO // January 19, 2017 at 12:08 pm // Reply

    But many say UA is a risk factor for CKD

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