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

2. 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?

3. 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

4. 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?

5. 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

6. 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

7. 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

8. 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

9. 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 ( mg daily)
Only 2 trials were placebo-controlled studies

10. 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)

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

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

13. 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

14. 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

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

16. 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?

17. 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)

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

19. 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