Urate-Lowering Therapy Linked to Reduced Kidney Disease Progression and Mortality in CKD

Initiation of urate-lowering therapy (ULT) was associated with significantly lower risks of kidney disease (KD) progression, end-stage KD (ESKD), and mortality among patients with chronic KD (CKD) and hyperuricemia, according to a large real-world study published in Signal Transduction and Targeted Therapy. The findings contribute to an evolving and often debated evidence base regarding the role of uric acid reduction in CKD management.¹

Hyperuricemia, commonly observed in CKD due to reduced renal excretion, is historically considered a modifiable risk factor for disease progression. However, prior clinical trials have produced inconsistent results regarding whether pharmacologic urate-lowering improves renal outcomes. The current study leverages a large, longitudinal data set and advanced causal inference methods to help clarify this relationship.^1,2

ULT Associated With Lower Risk of Kidney Decline and ESKD

The study evaluated 56,936 adults with CKD and hyperuricemia using a target trial emulation framework applied to the China Renal Data System. Across 269,831 person-trials, investigators compared outcomes among patients initiating ULT vs those receiving supportive care alone.¹

At 3 years, the cumulative incidence of the primary composite outcome—defined as a sustained 40% or greater decline in estimated glomerular filtration rate or progression to ESKD—was 19.69% in the ULT group compared with 23.22% in the control group, corresponding to a risk difference of –3.53% (95% CI, –5.25% to –1.94%).¹

Notably, ULT showed reduced risks of individual clinically meaningful outcomes, including ESKD (risk difference, –1.88%; 95% CI, –3.28% to –0.45%), all-cause mortality (–2.25%; 95% CI, –3.02% to –1.51%), and cardiovascular mortality (–0.69%; 95% CI, –1.33% to –0.05%). These benefits were consistent across subgroups stratified by age, baseline kidney function, and comorbidities such as diabetes and hypertension, suggesting broad applicability in real-world CKD populations.¹

For pharmacists, these findings reinforce the importance of evaluating hyperuricemia not only as a comorbidity but also as a potential therapeutic target in CKD progression.

Consistent Benefits Across Urate-Lowering Agents

The study also assessed individual ULT agents, including allopurinol, febuxostat, and benzbromarone, and found similar associations with improved kidney outcomes across therapies. This suggests that the observed benefit may be driven by urate reduction itself rather than a drug-specific effect.¹

Importantly, no significant increase in adverse safety outcomes—including hypersensitivity or hepatotoxicity—was observed between treatment groups, supporting the tolerability of ULT in this population. This is particularly relevant for pharmacists managing polypharmacy in CKD, where medication safety and dose adjustments are critical. Pharmacists can play a central role in selecting appropriate agents, monitoring for adverse effects, and ensuring renal dose optimization.¹

Addressing Ongoing Controversy in CKD Management

Despite biologic plausibility linking hyperuricemia to kidney injury—via inflammation, oxidative stress, and endothelial dysfunction—the role of ULT in CKD remained controversial. Prior randomized trials did not demonstrate significant renal benefit with allopurinol, leading some guidelines to recommend against routine use solely for kidney protection.^2,3

However, the current study differs in scale, patient population, and methodology, capturing real-world treatment patterns and longer-term outcomes. Its findings align with emerging observational and mechanistic evidence suggesting that urate reduction may play a role in slowing CKD progression in select populations. Taken together, the data suggest that patient selection may be key, with greater benefit potentially observed in individuals with higher baseline uric acid levels or more advanced disease.⁴

Implications for Pharmacist-Led Care

The study has important implications for pharmacists involved in CKD management, particularly in ambulatory and interdisciplinary care settings.

First, pharmacists are well positioned to identify patients with hyperuricemia who may benefit from therapy, especially those with progressive CKD or comorbid gout. Routine monitoring of serum uric acid levels, alongside renal function, can help guide treatment decisions.

Second, pharmacists can support safe and effective ULT use by initiating and titrating therapy to target uric acid levels; monitoring for hypersensitivity reactions, particularly with allopurinol; adjusting doses based on kidney function; and managing drug interactions and adherence challenges. Finally, pharmacists can contribute to shared decision-making, helping patients understand the potential benefits and uncertainties surrounding ULT in CKD.

Clinical Outlook

Although randomized controlled trials remain necessary to definitively establish causality, this large real-world analysis provides compelling evidence that ULT may reduce the risk of kidney disease progression and death in patients with CKD and hyperuricemia.

As the CKD treatment landscape continues to evolve—alongside established therapies such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and renin-angiotensin system blockers—urate-lowering strategies may represent an additional, targeted approach for select patients.⁴

For pharmacists, integrating these emerging data into clinical practice will require careful patient selection, ongoing monitoring, and collaboration with the broader care team to optimize outcomes in this high-risk 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(1):399. doi:10.1038/s41392-025-02497-0

2. Badve SV, Pascoe EM, Tiku A, et al; CKD-FIX Study Investigators. Effects of allopurinol on the progression of chronic kidney disease. N Engl J Med. 2020;382(26):2504-2513. doi:10.1056/NEJMoa1915833

3. Doria A, Galecki AT, Spino C, et al; PERL Study Group. 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

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