Urate-Lowering Therapy Linked to Reduced Kidney Progression in Patients With CKD, Hyperuricemia

Urate-lowering therapy (ULT) was associated with significantly lower risk of kidney disease progression and mortality in patients with stage 3 or higher chronic kidney disease (CKD) and hyperuricemia, according to study findings published in Signal Transduction and Targeted Therapy. The findings challenge conclusions from recent randomized controlled trials and suggest that treating hyperuricemia may benefit patients with CKD.¹

Study Design and Key Findings

Investigators conducted a cohort study using a sequential target trial emulation framework to evaluate composite kidney outcomes in patients with CKD and hyperuricemia. The analysis included 269,831 eligible person-trials representing 56,936 unique individuals from the China Renal Data System database. Participants had stage 3 or higher CKD with serum uric acid levels above 7 milligrams per deciliter (mg/dL) in men or 6 mg/dL in women and had previously received supportive care.¹

The primary outcome was a composite kidney outcome defined as greater than a 40% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease (ESKD). The 3-year cumulative incidence rates were 19.69% in the ULT group and 23.22% in the control group, with a risk difference of −3.53% (95% CI, −5.25% to −1.94%). This represented an 18% relative risk reduction.¹

For secondary outcomes, the estimated 3-year risk differences favored ULT: −1.88% (95% CI, −3.28% to −0.45%) for ESKD, −2.25% (95% CI, −3.02% to −1.51%) for all-cause mortality, and −0.69% (95% CI, −1.33% to −0.05%) for cardiovascular mortality. Sensitivity analyses yielded consistent results, including separate analyses for allopurinol (Zyloprim; Casper Pharma LLC), febuxostat (Uloric; Takeda Pharmaceuticals), and benzbromarone.¹

Context and Clinical Controversy

Hyperuricemia affects approximately 24% of patients with CKD in the United States, compared with 11.9% in the general population. The prevalence intensifies dramatically with advancing CKD stage, demonstrating a nearly 10-fold higher rate in stages 3 to 5 than in stage 1. Despite observational evidence linking hyperuricemia to CKD progression, clinical trial evidence has been mixed.^1,2

Two large placebo-controlled trials published in June 2020—the Preventing Early Renal Loss in Diabetes (PERL) trial (NCT02017171) and the Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase (CKD-FIX)—showed no benefit from allopurinol on CKD progression endpoints. Both trials enrolled participants with broad age ranges and widely varying baseline kidney function. They used eGFR slope as a surrogate endpoint rather than hard kidney outcomes.^3,4

In the CKD-FIX trial, 369 patients with stage 3 or 4 CKD without a gout history were randomly assigned to allopurinol or placebo. The mean difference in eGFR change from baseline to 104 weeks was 3.1 milliliters per minute per 1.73 m² of body-surface area (95% CI, −0.9 to 7.0), a difference that was not statistically significant. The PERL trial enrolled 530 patients with type 1 diabetes and showed similarly neutral results after 3 years.^3,4

Following these trials, the Kidney Disease Improving Global Outcomes guideline recommended against routine use of urate-lowering agents in CKD patients with asymptomatic hyperuricemia for slowing disease progression, citing low certainty of evidence.⁵

Recent Evidence Supporting ULT Benefits

More recent studies have provided counterevidence. A January 2025 study published in JAMA Internal Medicine evaluated 14,792 patients with gout and stage 3 CKD. The study found that achieving serum urate levels below 6 mg/dL with ULT was not associated with increased risk of severe or end-stage kidney disease progression compared with those who did not achieve this target. The 5-year risk of severe or end-stage kidney disease was 10.32% for those who achieved the target serum urate level and 12.73% for those who did not. The adjusted risk difference was –2.41% (95% CI, –4.61 to –0.21%), while the adjusted HR was 0.89 (95% CI, 0.80 to 0.98).⁶

The findings suggest that lowering serum urate to recommended targets is well tolerated in patients with gout and CKD stage 3. According to the investigators, the results support optimizing ULT use to achieve target levels, potentially benefiting both gout control and kidney outcomes.⁶

Pharmacist Implications: How ULT Can Be Managed in Patients With CKD

Pharmacists play critical roles in managing ULT in patients with CKD. Key considerations include appropriate dosing based on renal function, agent selection considering comorbidities, patient education on treatment goals and adherence, monitoring for drug interactions, and assessing for adverse effects.

For patients with moderate to severe CKD, allopurinol should be initiated at doses of 100 mg or less to avoid hypersensitivity syndrome, though doses can be safely increased to achieve target serum urate levels. Patients with CKD may require allopurinol doses of 300 mg per day or higher to reach therapeutic targets. Febuxostat undergoes primarily hepatic metabolism, allowing for simplified dosing in mild to moderate kidney failure.⁷

The current Kidney Disease Improving Global Outcomes guideline recommends against routine ULT for asymptomatic hyperuricemia in CKD. However, this new real-world evidence suggests potential benefits warrant reconsideration. Pharmacists should stay informed about evolving evidence as larger randomized clinical trials with refined designs are conducted.^1,5

The investigators emphasized that treating hyperuricemia may be beneficial for patients with CKD, particularly those at high risk for progression. Further high-quality randomized controlled trials are needed to definitively establish the role of ULT in this population.

REFERENCES

1. Nie S, Zhou S, Chen R, et al. Urate-lowering therapy and kidney outcomes in patients with chronic kidney disease and hyperuricemia. Signal Transduct Target Ther. 2025;10:399. doi:10.1038/s41392-025-02497-0

2. Wu S, Xue W, Yu H, et al. Serum uric acid levels and health outcomes in CKD: a prospective cohort study. Nephrology Dialysis Transplantation. 2024;39(3):510-519. doi:10.1093/ndt/gfad201

3. 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 doi:10.1056/NEJMoa1916624

4. 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 doi:10.1056/NEJMoa1915833

5. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney International. 2024;105(4):S117-S314. doi:10.1016/j.kint.2023.10.018

6. Wang Y, Dalbeth N, Terkeltaub R, et al. Target serum urate achievement and chronic kidney disease progression in patients with gout and kidney disease. JAMA Intern Med. 2025;185(1):74-82. doi:10.1001/jamainternmed.2024.6212