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.

Study Overview

• Status: Terminated
• Conditions: Chronic Kidney Diseases; Hyperuricemia
• Intervention / Treatment: Drug: Allopurinol

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Allopurinol; 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.	Drug: Allopurinol; Allopurinol dosed to target uric acid levels of 3-5 mg/dL.
No Intervention: Standard of Care Control; The treatment arm will be compared to a standard of care arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
eGFR Change	Change in Cys-C eGFR over time	The difference in Cystatin C eGFR between baseline and 6 months will be measured
eGFR Change	Change in Creatinine eGFR over time	The difference in Creatinine eGFR between baseline and 6 months will be measured

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Uric Acid Change	Change in Serum Uric Acid	The difference in Serum Uric Acid between baseline and 6 months will be measured
Systolic Blood Pressure	Change in systolic blood pressure	The difference in clinic systolic blood pressure between baseline and 6 months will be measured
Diastolic Blood Pressure	Change in diastolic blood pressure	The difference in clinic diastolic blood pressure between baseline and 6 months will be measured

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum High Sensitivity C-reactive Protein (Hs-CRP)	Compare the mean difference of serum hs-CRP from baseline to 6 months between groups	Serum hs-CRP will be measured at baseline and 6 months
Interleukin 18	Change in interleukin 18	Serum interleukin 18 will be measured at baseline, 3 months, and 6 months
Serum Nlrp3	Change in serum Nlrp3	Serum Nlrp3 will be measured at baseline, 3 months, and 6 months
Urine Neutrophil Gelatinase-associated Lipocalin (NGAL)	Change in urine NGAL	Urine NGAL will be measured at baseline, 3 months, and 6 months
Urine Endothelin-1 (ET-1)	Change in urine ET-1	Urine ET-1 will be measured at baseline, 3 months, and 6 months
Urine Kidney Injury Molecule-1 (KIM-1)	Change in urine KIM-1	Urine KIM-1 will be measured at baseline, 3 months, and 6 months
Urine N-acetyl-Beta-D-Glucosaminidase (NAG)	Change in urine NAG	Urine NAG will be measured at baseline, 3 months, and 6 months

Collaborators and Investigators

• Sponsor: Virginia Commonwealth University
• Investigators: Principal Investigator: Cristin Kaspar, MD, Virginia Commonwealth University

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2019
• Primary Completion (Actual): October 7, 2020
• Study Completion (Actual): October 7, 2020

Study Registration Dates

• First Submitted: March 5, 2019
• First Submitted That Met QC Criteria: March 5, 2019
• First Posted (Actual): March 6, 2019

Study Record Updates

• Last Update Posted (Actual): May 27, 2021
• Last Update Submitted That Met QC Criteria: May 4, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic; Hyperuricemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Antioxidants; Free Radical Scavengers; Gout Suppressants; Allopurinol
• Other Study ID Numbers: HM20014698

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes