Uric Acid and the Kidney - Is There a Role for Urate Lowering?
Daniel E. Weiner, MD, MS, FNKF
The author will discuss the topic of this article at the National Kidney Foundation's 2013 Spring Clinical Meetings in Orlando, Fla., April 2-6.
In a report published 115 years ago in the Journal of the American Medical Association, N. S. Davis Jr, MD, Professor of Medicine at Chicago Medical College, published a brief treatise titled “The Cardiovascular and Renal Relations and Manifestations of Gout.” In this article, he wrote: “High arterial tension in gout is due in part to uric acid or other toxic substances in the blood which increase the tonus of the arterioles.”
He also observed: “The commonest and most characteristic cardiac change associated with gout is hypertrophy.” Dr. Davis concluded: “These various changes in the kidneys, arteries and heart may occur in podagra or characteristic gout, but are more frequently seen independent of it and often themselves constitute the most marked manifestations of a gouty diathesis.”
Jumping forward to 2013, we have come full circle, again recognizing gout, and, more specifically, hyperuricemia, as a state that likely predisposes to cardiovascular disease (CVD) and chronic kidney disease (CKD); however, we have yet to prove Dr. Davis' supposition that uric acid itself increases vascular risk in people.
To date, many but not all cohort studies examining the relationship between hyperuricemia and kidney disease outcomes suggest that there may be direct causality intertwined within the associations among uric acid, CKD, and CVD; however, hyperuricemia is common in individuals with other kidney disease and CVD risk factors, including the components of the metabolic syndrome and sedentary lifestyle factors. Additionally, uric acid is handled by the kidney and correlates with glomerular filtration rate (GFR), further affecting the ability to interpret cohort study data.
Evidence from experimental models and human studies
To begin to answer this question—and ultimately the corollary that treatment of hyperuricemia will reduce kidney disease and CVD risk—initial lessons can be drawn from experimental models and cohort and clinical studies.
Most notably, in one experimental model where rats were given a uricase inhibitor to promote mild hyperuricemia, systemic hypertension developed within three weeks and improved following administration of a xanthine oxidase inhibitor, with resultant lowering of serum uric acid. Data from this study also suggested that renal vasoconstriction, up-regulation of the renin-angiotensin-aldosterone system and decreased nitric oxide availability may be complicit in systemic hypertension.
A second set of clues on whether hyperuricemia may be causal of kidney disease and CVD has emerged from studies of healthy adults. In one recent publication, Bellomo and colleagues evaluated 900 healthy adult blood donors and demonstrated that higher serum uric acid levels were associated with a modestly increased risk of estimated GFR decline, while, in a large apparently healthy Taiwanese cohort, higher uric acid levels were associated with an increased risk of CVD events.
A third clue comes from the most notable clinical trial in this field to date. In this randomized, double-blind, placebo-controlled, crossover trial that included 30 adolescents, allopurinol used for lowering uric acid levels was associated with better blood pressure control. More substantial studies are ongoing although none are sufficiently long in duration or adequately powered to determine if treatments specifically targeting uric acid lowering will result in improved kidney and CVD outcomes.
Finally, several small clinical trials in at risk populations have shown a benefit on surrogate outcomes, including small differences in GFR loss associated with allopurinol use.
Critically, hyperuricemia is a readily modifiable risk factor that can be treated with lifestyle changes as well as medications. Therefore, defining the relationship among uric acid, kidney disease, and CVD has significant clinical importance. Interestingly, this is one particular question where the human physiology may be best elucidated through clinical intervention trials.
Unfortunately, to date, there are no adequately powered clinical trials that explore harder clinical outcomes currently underway, keeping the answer to this question elusive. Similarly, the design and implementation of this trial remains a difficult concept, as identifying the population most likely to gain significant benefit from uric acid lowering will be critical to a potential clinical trial and, ultimately, clinical successes.