Anthony J. Bleyer, MD
Wake Forest School of Medicine

Nephrologists recently gathered for the virtual American Society of Nephrology’s (ASN) Kidney Week 2021 to discuss the latest research, insights, and innovations in kidney care. This year’s conference had a compelling program comprising more than 3000 abstracts, including presentations on COVID-19 with a global focus on kidney health.
 
Anthony J. Bleyer, MD, professor of nephrology in the Department of Internal Medicine at the Wake Forest School of Medicine in Winston-Salem, North Carolina, provided his insight into, and key takeaways from, the most recent research on hyperuricemia presented at Kidney Week 2021.

Among the presentations on hyperuricemia at this year’s meeting, which abstracts were the most interesting or clinically impactful?

Like many other fields, nephrology research was affected by COVID-19, which resulted in fewer presentations on hyperuricemia than in prepandemic years.
 
An important presentation, however, in the context of the ongoing pandemic was the study on prevalence and outcomes associated with hyperuricemia in hospitalized patients with COVID-19.1 In this study, investigators from the Icahn School of Medicine at Mount Sinai, in New York City, included 834 adult patients with COVID-19 who were hospitalized and underwent at least 1 serum uric acid measurement. They evaluated the association between the first serum uric acid level and major adverse kidney events (defined as a composite of all-cause in-hospital mortality, renal replacement therapy, and 100% increase in serum creatinine from baseline), as well as markers of inflammation and cardiac injury.
 
The median first serum uric acid level was 5.9 mg/dL, and findings showed that doubling in serum uric acid level was associated with increased risk of major adverse kidney events (odds ratio [OR], 2.5 per doubling) and in-hospital mortality (OR, 1.7 per doubling). This was interesting because it suggests that serum uric acid level measurement obtained early in the COVID-19 disease course could serve as an important prognostic factor both in hospital and outpatient settings, and help us better identify patients with COVID-19 who may have poor outcomes. If a patient is identified early as an outpatient, it could be possible to intervene with COVID-19 treatments before their symptoms worsen based on measurement of uric acid levels.
 
This was a retrospective study, and future studies will need to collect data prospectively to reduce the risk of bias. It may be helpful to measure serum uric acid levels at the time of hospital admission or when patients are seen in the clinic and tested for COVID-19.
 
Another exciting study involved the use of contrast-enhanced ultrasound imaging as a diagnostic tool for early detection of renal injury caused by hyperuricemia.2 In this study, the investigators found a lower peak intensity value in renal cortical perfusion and prolonged time to reach peak intensity in a hyperuricemic rodent model (with hyperuricemia induced by feeding a mixture of adenine and potassium oxonate for up to 4 weeks) compared with control rats at 1 week and 4 weeks. The changes were more pronounced at 4 weeks, suggesting a greater impact on blood flow to the kidney.
 
The same investigators then went on to evaluate patients with stages 1 to 4 chronic kidney disease vs healthy volunteers. Similar to the findings seen in the rodent model component of the study, patients with stage 1 disease showed a decrease in the peak intensity in renal cortical perfusion compared with the control group. This decreased progressively in patients with more severe chronic kidney disease. The time to peak intensity also lengthened progressively with more advanced kidney disease.
 
This new imaging technique could be very helpful in our ability to diagnose chronic kidney disease and better determine prognosis. We need better biomarkers of activity and progression of kidney disease, and I hope that this technique will be a useful tool in the future.

Another noteworthy study3 (abstract PO1812) was a meta-analysis of interventional trials with urate-lowering therapy in individuals with asymptomatic hyperuricemia. The study showed that uric acid-lowering treatment of these patients may be beneficial in those with elevated creatinine and blood pressure, and decreased estimated glomerular filtration rate (eGFR). Can you provide your perspective on these study results and comment on research on the horizon for early detection and treatment of hyperuricemia?

There has always been an interest in the potential benefits of the treatment of asymptomatic hyperuricemia. However, randomized clinical trials have disappointedly shown no benefit. Most of these studies have been small in nature with relatively short-term follow-up.
 
A number of years ago, a large study found that veterans (≥40 years of age) who were on allopurinol had lower mortality rates than those who were not,4 with a hazard ratio (HR) of 0.77 after adjusting for other prognostic factors. A subsequent study in the general population showed a similar result (HR, 0.89), and the risk of mortality was even lower among individuals with gout (HR, 0.81).5 However, clinical trials evaluating the efficacy of reducing uric acid levels have not corroborated these findings.6,7 
 
More recently, 2 short-term clinical trials evaluated whether lowering uric acid levels with allopurinol was associated with improvement in chronic kidney disease outcomes. Unfortunately, in both studies, allopurinol had no beneficial effects on renal function.6,7
 
This recent meta-analysis conducted by researchers who are respected in the field showed really provocative data.3 Patients who received uric acid-lowering treatment had higher eGFR along with nonsignificant decreases in carotid intima-media thickness, which are both positive findings. Nonetheless, high-sensitivity C-reactive protein was also higher, which is unfavorable.
 
This study, although interesting, did not provide enough data for us to prescribe urate-lowering therapy to patients with asymptomatic hyperuricemia. The existing randomized trials were not beneficial in slowing progression of chronic kidney disease.6,7 Hence, I think it will be difficult to move forward from this meta-analysis to randomized trials. Current recommendations are against the treatment of asymptomatic hyperuricemia,8 and this study should not lead us to treat asymptomatic hyperuricemia.



Hyperuricemia is often a risk factor/comorbid condition in the context of other conditions such as gout, hypertension, diabetes, chronic kidney disease, and heart failure. What insights did you gain from your recent studies that evaluated hyperuricemia in these settings?

At Kidney Week, I presented a large cross-sectional study in which we evaluated risk factors and outcomes of gout in patients undergoing dialysis using US Renal Data System (USRDS) data including nearly all Medicare patients on chronic outpatient dialysis.9 We compared patients who were dialysis dependent and had at least 1 claim for gout with those without gout in 2017.
 
Of nearly 300,000 patients, 15% had at least 1 gout claim following initiation of chronic outpatient dialysis. Patients who had gout (vs no gout) were more likely to be men (62% vs 54%) and had other comorbidities including diabetes (67% vs 62%), hypertension (93% vs 74%), and cardiovascular conditions (heart failure [49% vs 30%], ischemic heart disease [49% vs 30%], peripheral vascular disease [32% vs 22%], stroke [12% vs 8%], acute myocardial infarction [7% vs 3%], and angina [4% vs 2%]). The 3 most significant factors associated with gout diagnosis were older age (OR, 4.23 for ≥65 vs <65 years), previous transplant (OR, 2.37), and comorbid hypertension (OR, 2.71). Additionally, their risks of hospitalization and mortality were 11% and 9% higher, respectively, than those of patients without gout within a year after diagnosis.
 
The key point from our study is that gout still occurs, even in dialysis patients. Gout is something that we need to be observant and ask our patients about because it can really affect quality of life in our patients. More importantly, it is treatable. We have a number of therapeutic options for gout, though they must be used carefully in patients with end-stage kidney disease.

Have you treated patients with COVID-19-related acute kidney injury (AKI), and have you evaluated serum uric acid levels in these patients?

Yes, I have treated patients with COVID-19-related AKI. However, we have not looked at uric acid levels. In terms of AKI, COVID-19 vaccinations and treatments, such as monoclonal antibodies, have improved outcomes for COVID-19 and reduced the occurrence of COVID-related AKI.

Are there any final comments that you would like to add about Kidney Week 2021?

I think there is indirect evidence that high uric acid levels may have deleterious effects on the kidney, but no studies have definitively shown that treatment of hyperuricemia could be beneficial. The meta-analysis showed that treatment of asymptomatic hyperuricemia could potentially be beneficial, but based on the results of prior randomized trials, there is no indication for treatment of asymptomatic hyperuricemia at this time.3-8
 
Gout remains a prevalent disorder and is especially common in individuals with chronic kidney disease. We need to move away from thinking of gout as a lifestyle disease due to consumption of purine-rich foods and instead realize the high contribution of decreased renal excretion of uric acid as the primary cause of gout.10 Treatment with urate-lowering therapy can be highly effective in improving quality of life in these patients.
 
I think there was less research in hyperuricemia and kidney disease over the last year due to the effects of COVID-19. I am hoping that the incidence of COVID-19 will markedly decrease, and that we will be able to increase research into the causes and treatment of kidney disease in the future.

Key Takeaways

  • In a study of hospitalized adult patients with COVID-19, a doubling in serum uric acid level was associated with increased risk of major adverse kidney events and in-hospital mortality, suggesting serum uric acid level measurement early in the COVID-19 disease course could serve as an important prognostic factor to identify patients with COVID-19 who may have poor outcomes. However, the findings will need to be confirmed with further studies.
  • Contrast-enhanced ultrasound imaging appears to be useful for detection of renal injury caused by hyperuricemia, and its associated parameters could potentially serve as much needed markers in chronic kidney disease.
  • A new study suggested that treating asymptomatic hyperuricemia with uric acid-lowering treatment may be beneficial in patients with elevated creatinine and blood pressure, and decreased eGFR. However, this meta-analysis was not concordant with recent randomized clinical trials, which showed no benefit from treating asymptomatic hyperuricemia in chronic kidney disease. Current recommendations are against the treatment of asymptomatic hyperuricemia.
  • Among nearly 300,000 patients undergoing dialysis according to the USRDS, 15% had gout. Within a year of diagnosis, patients with gout had higher risk of hospitalization and mortality than patients without gout, highlighting the need to monitor for gout in patients undergoing dialysis.

This Q&A was edited for clarity and length.

Disclosure

Anthony Bleyer, MD, reported affiliations with Horizon Therapeutics plc.

References

  1. Chauhan K, Pattharanitima P, Piani F, et al. Prevalence and outcomes associated with hyperuricemia in hospitalized patients with COVID-19. Presented at: Kidney Week 2021, November 2-7, 2021. Abstract PO0073.
  2. Fan Y, He L, Li Z, et al. Evaluation of changes in renal microperfusion in hyperuricemic-induced kidney injury by contrast-enhanced ultrasound imaging. Presented at: Kidney Week 2021, November 2-7, 2021. Abstract PO2427.
  3. Gala DN, Said KS, El-Shahat NA, et al. Potential benefits of asymptomatic hyperuricemia treatment: a systematic review and meta-analysis of randomized control trials. Presented at: Kidney Week 2021, November 2-7, 2021. Abstract PO1812.
  4. Luk AJ, Levin GP, Moore EE, Zhou XH, Kestenbaum BR, Choi HK. Allopurinol and mortality in hyperuricaemic patients. Rheumatology (Oxford). 2009;48(7):804-806. doi:10.1093/rheumatology/kep069
  5. Dubreuil M, Zhu Y, Zhang Y, et al. Allopurinol initiation and all-cause mortality in the general population. Ann Rheum Dis. 2015;74(7):1368-1372. doi:10.1136/annrheumdis-2014-205269
  6. Badve SV, Pascoe EM, Tiku A, et al. Effects of allopurinol on the progression of chronic kidney disease. N Engl J Med. 2020;382(26):2504-2513. doi:10.1056/NEJMoa1915833
  7. Doria A, Galecki AT, Spino C, et al. Serum urate lowering with allopurinol and kidney function in type 1 diabetes. N Engl J Med. 2020;382(26):2493-2503. doi:10.1056/NEJMoa1916624
  8. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthritis Care Res (Hoboken). 2020;72(6):744-760. doi:10.1002/acr.24180
  9. Bleyer AJ, Zhang Y, Kshirsagar OS, Marder B, LaMoreaux B. Risk factors and outcomes of gout in dialysis patients: a cohort study of the United States Renal Data System (USRDS). Presented at: Kidney Week 2021, November 2-7, 2021. Abstract PO0792.
  10. Ichida K, Matsuo H, Takada T, et al. Decreased extra-renal urate excretion is a common cause of hyperuricemia. Nat Commun. 2012;3:764. doi:10.1038/ncomms1756

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Reviewed December 2021