Reanalysis of CARES study to investigate the changes of estimated glomerular filtration rate after long-term febuxostat or allopurinol treatment in gout patients

Lead Investigator: Byeongzu Ghang, Jeju National University Hospital
Title of Proposal Research: Reanalysis of CARES study to investigate the changes of estimated glomerular filtration rate after long-term febuxostat or allopurinol treatment in gout patients
Vivli Data Request: 7388
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Hyperuricemia is elevated uric acid in the blood, above a certain level, crystal deposits may occur leading to pain and swelling in the joints known as gout. Hyperuricemia is also associated with various health conditions such as heart disease, diabetes mellitus, and kidney disease. Of these, chronic kidney disease (CKD) has been identified as a major public health concern worldwide. Hyperuricemia is significantly associated with development and progression of CKD. Several possible mechanisms explaining this relationship have been suggested, however, it is still unclear whether hyperuricemia plays a causative role in the progression of CKD, or is an indirect marker of decreased kidney function.
Under the hypothesis that hyperuricemia is a potentially modifiable risk factor for the progression of CKD, there has been an expectation that the control of hyperuricemia using urate-lowering therapy (ULT) will have a beneficial effect on slowing the progression of CKD. There have been numerous small, single-center studies that have shown that use of ULT delayed CKD progression in patients with hyperuricemia. However, three recent multicenter, randomized controlled trials, not targeting gout patients, have not shown beneficial effect of a ULT on slowing the progression of CKD. Therefore, there is controversy over the role of ULT in the progression of CKD.

Statistical Analysis Plan:

I hypothesize that the effect of ULTs on progression of CKD in patients with asymptomatic hyperuricemia and gout patients is different, and that the control of hyperuricemia using ULT will have a beneficial effect by removing deposited uric acid crystal from the kidney in gout patients. We investigated whether ULT has a beneficial effect on the progression of CKD in gout patients, using the data of a large, multicenter, randomized controlled trial.

Therefore, data from large gout population who received long-term ULT (febuxostat or allopurinol) are needed. I hope to identify changes in kidney function in these patients. To check kidney function, we will analyze the change in the estimated glomerular filtration rate (eGFR) during the study period, determined by the Chronic Kidney Disease Epidemiology (CKD-EPI) creatinine equation.

Because kidney function fluctuates depending on the situation, in order to investigate this, the outcome of interest is eGFR change defined as the intraindividual variability in eGFR levels. The linear mixed model with a random intercept and slope is used to estimate eGFR change over time in each patient. The intercept and slope are both fitted as random effects to address the inter-patient differences at baseline and the different rates of eGFR change during follow-up. I will calculate the slope of eGFR to time from the baseline (in years) using eGFR as the dependent variable, and measurement time from the baseline as the independent variable. We use the slope as the annual rate of change in eGFR.

Comparisons of baseline characteristics between those with CKD progression and CKD progression delayed groups will be made using the Pearson’s chi-squared test, Fisher’s exact test, Student’s t-test, or Wilcoxon rank sum test according to the type of variable.
Multivariable binary logistic regression will be used to evaluate the association between prognostic factors and CKD progression. Subgroup analyses will be performed within prognostic factors for the better understanding of average UA effects. Interaction between the average UA and each subgroup will be tested using a two-sided Wald test in logistic regression.

Requested Studies:

A Multicenter, Randomized, Active-Control, Phase 3B Study to Evaluate the Cardiovascular Safety of Febuxostat and Allopurinol in Subjects With Gout and Cardiovascular Comorbidities
Data Contributor: Takeda
Study ID: NCT01101035
Sponsor ID: TMX-67_301

Public Disclosures:


2. Byeongzu Ghang, Jinseok Kim. Effects of long-term febuxostat or allopurinol on the progression of chronic kidney disease. Journal of Rheumatic Diseases Vol. 29, Suppl. 1, May, 2022 p271 O-54.