Effects of Uric acid- lowering therapy on renal outcomes: a systematic review and meta-analysis Nephrol Dial Transplant (2014) 29: 406-413 Vaughan Washco DO

Background: Uric acid (UA) can act as an antioxidant in an extracellular environment, however intracellular UA plays an inflammatory role. Hyperuricemia- Associated with HTN, CHD, Stroke, DM2, Metabolic Syndrome. CKD- association (secondary to decreased filtration) vs casual factor- pathogenic role?

Background: Pathophysiology- Animal studies: crystal independent dependent process that leads to afferent arteriole thickening (inflammatory process, ROS) affecting autoregulation- ultimately glomerular perfusion. Leads to glomerulosclerosis and later interstitial fibrosis

Introduction: Therapies for slowing the progression of CKD are limited- treating underlying cause (DM/HTN) only provide modest relative risk reduction of adverse renal and CV outcomes. Are we failing to identify and target appropriate risk factors for progression of CKD? Uric acid as a novel and potentially modifiable risk factors?

Introduction: Aim of this study- systematic review of randomized controlled trials to evaluate the benefit and risks of uric acid lowering therapy. Focus on Renal outcomes and serious adverse events

Methods: Inclusion: RCTs, compared a uric acid lowering agent with placebo, no treatment or standard therapy, followed participants for at least 3 months, and reported change in GFR, CrCL, serum Cr, doubling of serum Cr, or progression to ESRD. Hyperuricemia was not an eligibility criterion. Exclusion- patients with ESRD. Search Engines; Medline, EMBASE, and CENTRAL Methodological Quality of each study was assessed using a risk of bias assessment tool Data extraction carried out by 2 authors- disagreements resolved via consultation with 2 other authors

Methods: Primary outcome- change in kidney function from baseline (GFR or Cr) Secondary- Progression to ESRD, doubling of serum Cr, or worsening of kidney function, change in proteinuria, change in BP, uric acid levels, all cause mortality, major CV events, and all cause hospitalizations

Statistical Analysis: Tx effects, summarized using random effects meta-analysis Outcomes expressed as risk ratio with 95% CI and Mean Differences Heterogeneity was also estimated

Results: 8 trials found after screening for above inclusion and exclusion criteria- 476 patients, median f/u of 11 months 6 trials- patients with varying degree of CKD 2 trials- normal or mildly decreased kidney function No kidney transplant recipients Allopurinol was the intervention agent (100-300 mg daily) Only 2 trials were placebo-controlled studies

Results: Primary Outcomes 5 trials reported data on end of tx GFR, 3 trials on serum Cr at end of follow up. No sig difference in the change in GFR from baseline between the allopurinol and control arms. Subgroup analysis for just CKD- also no sig difference Meta analysis of 3 trials (130 participants- all with CKD) – showed change in serum Cr from baseline was in favor of allopurinol at 3 months and 6 months (P 0.03, 0.003)

Forrest Plot: Allopurinol vs Control Arm Effects on Change in GFR from baseline

Forrest Plot: Allopurinol vs Control Arm Effects on Change in Serum Cr From Baseline

Results: Secondary Outcomes Progression of ESRD? No reported events of reaching ESRD in 4/6 trials performed in the CKD patients, in the remaining 2 allopurinol did not significantly alter risk. Enough follow up time to determine effects on progression to CKD? Very little data on worsening kidney function, doubling of serum Cr No significant difference on change in proteinuria

Results: Secondary Outcomes No significant difference in change in BP. Significantly reduced serum uric acid in the allopurinol tx groups- but high level of heterogeneity in treatment. Mortality, hospitalization, and major CV events reported in a single trial- meta analysis not possible

Results: Adverse Effects No significant difference in allopurinol vs control arms- medication side effects? No mention of Steven Johnson syndrom, TEN, aplastic anemia, throbocytopenia

Discussion: Numerous observational cohort studies showing an association between UA and both CKD and ESRD Unclear of the effects of treatment with allopurinol vs no treatment or placebo; ie- GRF, Cr, proteinuria, porgression of ESRD, BP, hospitalization, and CV events. Causative role vs biomarker for reduced renal function?

Discussion: Allopurinol therapy lowered serum Cr in 3 trials (small number of people- 130) however effects on GFR, proteinuria , and risks of progression to ESRD was uncertain Strengths- comprehensive overview of the evidence, risk of assessment, and inclusion of only RCTs However- small number of trials, variable duration of follow up, and clinical heterogeneity (ie- baseline kidney function, proteinuria)

Discussion: Only 2 trials were placebo controlled Lack of data on adverse effects of allopurinol No data on febuxostat

Conclusion: Evidence for the safety and efficacy of allopurinol as a renoprotective agent in CKD is limited to a small number of single center studies Insufficient evidence for widespread use of uric acid lowering therapy to slow the progression of CKD But- abundance of evidence of an association between UA and CKD progression from epidemiological and animal studies Obvious need for adequately powered, high quality, randomized placebo- controlled trials to draw a robost conclusion of the risks and benefits of an UA reducing agents in patients with CKD