Uric Acid Reduction as a Novel Treatment for Pediatric Chronic Kidney Disease

Aim 1. To determine the effect of Allopurinol treatment on renal function (glomerular filtration rate, GFR) in pediatric chronic kidney disease (CKD) patients with high uric acid levels (hyperuricemia). Aim 2. Establish whether Allopurinol treatment reduces Nlrp3 inflammasome and renal injury biomarkers.

Uric acid levels often rise when kidney function declines. Historically, high uric acid has not been treated unless the uric acid crystallizes in the joint space and causes clinical gout disease, more typically seen in adults. However, new research has shown that high uric acid levels are associated with the development of hypertension, inflammation, and both acute and chronic kidney injury. Adult patients on renal dialysis who have hyperuricemia also have higher mortality rates. In several adult and in one pediatric clinical trial of uric acid lowering therapy (with Allopurinol or Febuxostat), treatment has demonstrated a slower rate of renal function decline and improved blood pressure compared to placebo. The pediatric trial was a 4-month placebo controlled trial of Allopurinol, and showed positive improvement in renal function and blood pressure, but did not adequately control for potential confounders in the outcome. Two known confounders that influence renal function (glomerular filitration rate, GFR) in pediatric CKD are race and glomerular or non-glomerular disease etiology. This study is designed to control for these confounders and establish whether Allopurinol for 6 months of treatment to a goal range of 3-5 mg/dL will improve renal function compared to standard of care. The secondary outcome is to determine whether blood pressure is affected by the treatment and the magnitude of change of serum uric acid. This study will also explore whether Allopurinol treatment alters activation of the Nlrp3 inflammasome or renal injury biomarkers.

Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial.

Inclusion Criteria: Chronic Kidney Disease stage 1-5 Hyperuricemic (UA >= 5.5 mg/dL) Exclusion Criteria: Contraindication to Allopurinol Elevated baseline liver function tests Receiving acute or chronic dialysis Primary metabolic disorder Sickle cell disease Autosomal Dominant Polycystic Kidney Disease Cystinosis Bartter or Gitelman Disease Pregnant or nursing