Uric acid - a potent antioxidant with protective and toxic affects on renal function Free

Introduction

Sickle cell disease (SCD) is a recessive blood disease affecting about 300,000 newborns every year. SCD causes polymerization of deoxygenated hemoglobin resulting in tissue hypoxia and reperfusion injury leading to inflammation that contributes to pain crises and organ damage. Uric acid is the most abundant and potent plasma antioxidant. Epidemiologic, physiological, and animal studies suggest a protective effect of this antioxidant. Murine sickle cell models of hemolysis support his hypothesis. Too low uric acid levels are associated with multiple sclerosis, poor innate immunity, and inflammation. Chronic kidney disease (CKD) is a leading cause of death and morbidity in about 50% of adult sickle cell patients. Prior associative studies have led to the belief that an increase in uric acid concentrations may cause this decline in renal function. However, given its antioxidant properties, it is not known whether this increase in serum uric acid with kidney disease in SCD is a cause or an effect and may even be protective. To examine this question, we employed statistical models that account for the effects of a rise in uric acid concentrations on renal function over time. This study utilized the ASH Research Collaborative (ASH RC) Data Hub.

Methods After IRB approval, the ASH RC Data Hub was queried for basic demographics, sickle cell genotypes, uric acid measurements, and renal parameters. Time-Varying Effect Modeling (TVEM) estimated how the association between time-varying uric acid levels and renal markers (serum creatinine, estimated glomerular filtration rate (eGFR)) changed flexibly over the study period. Distributed Lag Non-Linear Models (DLNM) characterized lead-lag patterns between uric acid fluctuations and kidney outcomes to identify critical exposure windows where uric acid levels exerted their strongest influence. The earliest available serum uric acid and creatinine levels within 30 days of each other was used as the baseline pairs for these analyses. Severe disease was defined as SS or S Bthal0 genotypes. The CKD-EPI creatinine equation (2021) was used to calculate eGFR. Both models controlled for age, sex, and severe disease. Model selection was guided by evaluation of competing specifications using information criteria (e.g., AIC, BIC) to ensure optimal fit and interpretability. Analyses were performed using SAS version 9.4.

Results

Querying the ASH RC Data Hub found 12,773 attested SCD patients and their genotypes. We excluded labs within 14 days of emergency room visits or hospital stays, patients with no data after 1/1/2015, and patients with no uric acid values. There were 581 patients included for analysis, with 46% of these having two or more creatinine and uric acid paired values. Mean age was 36.8 years old, with 88.5% ≥18 years old. The sexes were nearly 50% each. The genotypes were 74.5% SS, 15.8% SC, and 1.9% Sthal0. Those with severe disease were 76.4%. Of those with less severe disease, 67 % were SC. Mean uric acid level was 6.3 (SD 2.31). TVEM modeling found that after three years, the effect of uric acid on eGFR suggested an increasingly protective trend. The confidence intervals (CIs), however, crossed zero precluding statistical significance in later years, possibly from smaller numbers of subjects, dropping from 84 subjects at year four to just 2 at year nine. The DLNM found a statistically significant protective uric acid range of 4.5 – 6.5 mg/d, with CIs not crossing zero. Uric acid levels over 9 mg/dl were associated with worsening eGFR. There was no difference between sexes or between severe vs non-severe disease.

Conclusions This study highlighted the importance of the ASH RC Data Hub for sickle cell research. Future work will examine other renal outcomes such as proteinuria, while controlling for additional variables such as hemolysis, red cell turnover, medications such as hydroxyurea and NSAIDs, and hospitalizations. In this pilot study of the time effect of changes in uric acid on renal function, DLNM analysis found a potentially protective range of uric acid levels on renal function. The TVEM analysis, although not reaching statistical significance, showed a steadily increasing trend for benefit of higher uric acid levels on renal function up to a value of about 9 mg/dL. Despite being limited by small numbers, these results, given uric acid's known functional role as a potent antioxidant, warrant further study.