National Kidney Month Spotlight: Uric Acid and Its Role in Chronic Kidney Disease

kidney cross section
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In light of National Kidney Month, Richard J. Johnson, MD, discusses the association between uric acid levels and risk for chronic kidney disease among patients with gout.

Gout is commonly viewed as a painful arthritis; however, its association with kidney disease deserves much more attention than it currently receives.

Research has shown that the association between gout and hyperuricemia and chronic kidney disease (CKD) is common.1  

Because CKD can be relatively silent, only approximately half of patients with gout report reduced kidney function (CKD stage 3 and higher).2 In patients presenting with CKD stage 3 and higher, approximately one-quarter to one-thirds of patients have gout, and 50% to 60% have hyperuricemia.3

Given the overlap of gout with kidney disease, it is really important for both rheumatologists and nephrologists to understand the consequences of gout and whether it may contribute to kidney damage.

When gout was first described, it was largely thought of as a major cause of CKD, and it was called “gouty nephropathy.” Studies have found that urate crystals were not only present in the joints and skin, but also in the outer medulla.2 In addition, “gouty nephropathy” was found in a significant percentage of patients who developed end-stage kidney failure before there were effective therapies for gout, coupled with reports that lowering uric acid could reduce the risk for kidney failure among patients with gout.

The “gouty nephropathy” hypothesis was dismissed in the 1980s, when it was pointed out that the majority of patients with gout who developed kidney diseases had other conditions that could account for the kidney disease, such as hypertension and aging, and that the focal deposition of the urate crystals could not account for the diffuse disease of glomerulosclerosis, arteriolosclerosis, and tubular injury that was commonly present.4 By the late 1980s, the role of uric acid in kidney disease was completely discarded.5

However, studies conducted in 2000 showed that increased serum uric acid in animals could accelerate chronic kidney disease.6 No uric acid crystals were present in the kidney and the effects were mediated by soluble uric acid. While uric acid had been viewed as an antioxidant, as it can inactivate peroxynitrite in animal models, increased uric acid levels were found to induce oxidative stress, cause endothelial dysfunction, activate the renin angiotensin system, and have proinflammatory effects, including activation of NK-KB and the inflammasome.7,8

Lowering Uric Acid Levels in CKD

The association of hyperuricemia with CKD has become an intensely debated topic. Epidemiologic studies documented that while an increase in serum uric acid can result from kidney disease, as two-thirds of uric acid is excreted by the kidney, serum uric acid can also be elevated before CKD develops.7 Numerous studies documented that a high serum uric acid often precedes and predicts CKD, especially in patients with type 2 diabetes. Pilot studies have also reported that lowering uric acid could slow kidney disease, and meta-analyses have also confirmed this potential benefit.9,10

Richard J. Johnson, MD

Two major clinical trials were published that spiked the curiosity of uric-acid researchers. The PERL study evaluated patients with type 1 diabetes and CKD stage 2 and 3, and found no benefit of lowering uric acid with allopurinol on the progression of kidney disease.11 Similarly, the CKD-FIX study found minimal benefit for lowering uric acid with allopurinol in patients with more advanced CKD (stage 3 and 4).12 In addition, a large clinical trial (the ALL-HEART) also reported that allopurinol provided no benefit in reducing cardiovascular events in patients with preexisting heart disease.13

Based on these research studies, many experts concluded that lowering uric acid should not be performed among with CKD, except to prevent gouty arthritis.14 Some experts even reported that asymptomatic hyperuricemia might be beneficial in patients with CKD,15 while others were concerned that treatments might increase mortality, especially since the CARES study found that febuxostat resulted in more cardiovascular mortality than did allopurinol.16

However, it is becoming apparent that while we can learn from these trials, the verdict of whether to treat uric acid in CKD is far from certain. A key aspect of the CKD-FIX and the PERL studies (as well as the ALL-HEART) were that they excluded patients with gout, which can make up one-thirds of the CKD population. Both studies also did not limit treatment to those with hyperuricemia. Both the ALL-HEART and CKD-FIX studies did not include serum uric acid as an inclusion criterion. So, there were many individuals who received treatment but did not have hyperuricemia. Both trials were also associated with high dropout rates.

Which Patients May Benefit From Urate-Lowering Therapy?

Overall, many experts believe that a “blanket treatment” of patients with CKD with uric acid lowering therapy is not indicated. However, there are important subgroups of patients who should be monitored and are likely to benefit from this treatment.17

The first group is patients with gout, as currently less than half of them are currently being adequately treated.17. There is now tantalizing evidence that the majority of patients with gout have urate crystals outside of their joints, with common sites being the coronaries, aorta, and kidney. The lesions in the blood vessels seem to correlate with sites of plaque and calcification and are consistent with both Mendelian randomization studies and meta-analyses suggesting that gout can increase cardiovascular mortality. Other studies have linked urate crystals in the kidney with the presence of kidney stones or ultrasound evidence for hyperechoic kidneys.18,19 Of concern, asymptomatic hyperuricemia may also be associated with silent crystal deposition in the joints and blood vessels, and most likely in the kidney as well.

The second group to consider treating with uric acid lowering includes individuals with urate crystalluria. Not only may this predispose individuals to intrarenal crystal localization, but crystals can activate inflammasomes in tubular cells, leading to local injury. Crystalluria is common in patients with overload hyperuricosuria, such as that which occurs with increased production or tissue turnover. Some patients have been found to harbor genetic polymorphisms in ABCG2 (the Q141 variant) that reduce intestinal uric acid excretion and increase its excretion through the kidney.20 Other risk factors include those with diabetes (who show increased uricosuria) and those with low urinary pH. Indeed, is it possible that reports of bicarbonate therapy can slow CKD may related to blocking crystalluria.

The third group to consider for treatment are patients with increased uric acid production inside their cells. Many pro-inflammatory and pro-oxidative effects of uric acid are intracellular, so elevations in xanthine oxidase may be important in driving the kidney injury. Of note, plasma xanthine oxidase appears to mark individuals with high intracellular xanthine oxidase activity, and preliminary studies suggest it can identify patients at risk for kidney disease and cardiovascular events.21 An elevated serum uric acid by itself may also carry a risk as it can be transported into the cell. However, there may be a downregulation of urate transporters in cells in the setting of chronic hyperuricemia that may counter these effects.

In summary, gout and kidney disease appear to have a very strong interrelationship, and there are strong experimental evidence suggesting uric acid may have a role in kidney disease. Large clinical trials excluded patients with gout (the group most likely at risk) and included patients with normal serum uric acid levels (the group least at risk). Future trials could benefit from including individuals with gout, uricosuria, and those with elevated plasma xanthine oxidase activity. Individuals with high serum uric acid who show signs of inflammation (such as high C-reactive protein levels) may also represent another group at risk.

Disclosure: Richard J. Johnson, MD, is a board member of the Gout Education Society and professor of medicine at the University of Colorado in Aurora, Colorado. Dr Johnson declared affiliations with Horizon Pharma, Colorado Research Partners, LLC, and Xortx Therapeutics, Inc.


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