Chronic Kidney Diseases, Hyperuricemia
Conditions
Brief summary
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.
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.
Interventions
DRUGAllopurinol
Allopurinol dosed to target uric acid levels of 3-5 mg/dL.
Sponsors
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 20 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| eGFR Change | The difference in Cystatin C eGFR between baseline and 6 months will be measured | Change in Cys-C eGFR over time |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Uric Acid Change | The difference in Serum Uric Acid between baseline and 6 months will be measured | Change in Serum Uric Acid |
| Systolic Blood Pressure | The difference in clinic systolic blood pressure between baseline and 6 months will be measured | Change in systolic blood pressure |
| Diastolic Blood Pressure | The difference in clinic diastolic blood pressure between baseline and 6 months will be measured | Change in diastolic blood pressure |
Other
| Measure | Time frame | Description |
|---|---|---|
| Urine Endothelin-1 (ET-1) | Urine ET-1 will be measured at baseline, 3 months, and 6 months | Change in urine ET-1 |
| Serum High Sensitivity C-reactive Protein (Hs-CRP) | Serum hs-CRP will be measured at baseline and 6 months | Compare the mean difference of serum hs-CRP from baseline to 6 months between groups |
| Urine N-acetyl-Beta-D-Glucosaminidase (NAG) | Urine NAG will be measured at baseline, 3 months, and 6 months | Change in urine NAG |
| Urine Kidney Injury Molecule-1 (KIM-1) | Urine KIM-1 will be measured at baseline, 3 months, and 6 months | Change in urine KIM-1 |
| Interleukin 18 | Serum interleukin 18 will be measured at baseline, 3 months, and 6 months | Change in interleukin 18 |
| Serum Nlrp3 | Serum Nlrp3 will be measured at baseline, 3 months, and 6 months | Change in serum Nlrp3 |
| Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) | Urine NGAL will be measured at baseline, 3 months, and 6 months | Change in urine NGAL |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Allopurinol: Allopurinol dosed to target uric acid levels of 3-5 mg/dL. | 7 |
| Standard of Care Control The treatment arm will be compared to a standard of care arm. | 7 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Medical change caused patient to no longer meet inclusion/exclusion criteria | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Allopurinol | Total | Standard of Care Control |
|---|---|---|---|
| Age, Continuous | 14.29 years STANDARD_DEVIATION 2.5 | 14.07 years STANDARD_DEVIATION 2.46 | 13.86 years STANDARD_DEVIATION 2.61 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 13 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment United States | 7 participants | 14 participants | 7 participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 6 Participants | 10 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 0 / 7 | 0 / 7 |
| serious Total, serious adverse events | 1 / 7 | 0 / 7 |
Outcome results
Primary
eGFR Change
Change in Cys-C eGFR over time
Time frame: The difference in Cystatin C eGFR between baseline and 6 months will be measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allopurinol | eGFR Change | 3.14 ml/min/1.73m^2 | Standard Deviation 3.716 |
| Standard of Care Control | eGFR Change | -0.29 ml/min/1.73m^2 | Standard Deviation 5.251 |
p-value: 0.1839t-test, 2 sided
Primary
eGFR Change
Change in Creatinine eGFR over time
Time frame: The difference in Creatinine eGFR between baseline and 6 months will be measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allopurinol | eGFR Change | 3.86 ml/min/1.73m^2 | Standard Deviation 7.798 |
| Standard of Care Control | eGFR Change | 0 ml/min/1.73m^2 | Standard Deviation 3.857 |
p-value: 0.3036t-test, 2 sided
Secondary
Diastolic Blood Pressure
Change in diastolic blood pressure
Time frame: The difference in clinic diastolic blood pressure between baseline and 6 months will be measured
Population: Follow up blood pressure data was not collected from one participant in the treatment group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allopurinol | Diastolic Blood Pressure | -7.33 mmHg | Standard Deviation 6.29 |
| Standard of Care Control | Diastolic Blood Pressure | 3.983 mmHg | Standard Deviation 7.543 |
p-value: 0.0022t-test, 2 sided
Secondary
Serum Uric Acid Change
Change in Serum Uric Acid
Time frame: The difference in Serum Uric Acid between baseline and 6 months will be measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allopurinol | Serum Uric Acid Change | -3.33 mg/dl | Standard Deviation 0.996 |
| Standard of Care Control | Serum Uric Acid Change | -0.46 mg/dl | Standard Deviation 0.964 |
p-value: 0.0001t-test, 2 sided
Secondary
Systolic Blood Pressure
Change in systolic blood pressure
Time frame: The difference in clinic systolic blood pressure between baseline and 6 months will be measured
Population: Follow up blood pressure data was not collected from one participant in the treatment group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allopurinol | Systolic Blood Pressure | -6.5 mmHg | Standard Deviation 13.126 |
| Standard of Care Control | Systolic Blood Pressure | 2.29 mmHg | Standard Deviation 6.264 |
p-value: 0.1421t-test, 2 sided
Other Pre-specified
Interleukin 18
Change in interleukin 18
Time frame: Serum interleukin 18 will be measured at baseline, 3 months, and 6 months
Other Pre-specified
Serum High Sensitivity C-reactive Protein (Hs-CRP)
Compare the mean difference of serum hs-CRP from baseline to 6 months between groups
Time frame: Serum hs-CRP will be measured at baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allopurinol | Serum High Sensitivity C-reactive Protein (Hs-CRP) | 1.66 mg/dL | Standard Deviation 3.724 |
| Standard of Care Control | Serum High Sensitivity C-reactive Protein (Hs-CRP) | -7.64 mg/dL | Standard Deviation 18.639 |
p-value: 0.3032t-test, 2 sided
Other Pre-specified
Serum Nlrp3
Change in serum Nlrp3
Time frame: Serum Nlrp3 will be measured at baseline, 3 months, and 6 months
Other Pre-specified
Urine Endothelin-1 (ET-1)
Change in urine ET-1
Time frame: Urine ET-1 will be measured at baseline, 3 months, and 6 months
Other Pre-specified
Urine Kidney Injury Molecule-1 (KIM-1)
Change in urine KIM-1
Time frame: Urine KIM-1 will be measured at baseline, 3 months, and 6 months
Other Pre-specified
Urine N-acetyl-Beta-D-Glucosaminidase (NAG)
Change in urine NAG
Time frame: Urine NAG will be measured at baseline, 3 months, and 6 months
Other Pre-specified
Urine Neutrophil Gelatinase-associated Lipocalin (NGAL)
Change in urine NGAL
Time frame: Urine NGAL will be measured at baseline, 3 months, and 6 months