Hyperuricemia and abnormal nocturnal dipping impact glomerular filtration rate in patients with sickle cell anemia
Authors: Jeffrey D. Lebensburger, Inmaculada Aban, Lee M. Hilliard, Daniel I. Feig
Journal: American Journal of Hematology (2021)

Patients with sickle cell anemia (SCA) are at increased risk for developing chronic kidney disease (CKD), and progression to end-stage renal disease is associated with increased morbidity and mortality. Identifying modifiable risk factors for CKD in childhood are a vital first step to ameliorate progression. Patients with SCA may have higher risk for CKD due to the unique renal pathophysiology associated with chronic heme exposure and sickling of red blood cells; however, it is important to evaluate established risk factors associated with CKD in non-SCA populations. Hyperuricemia and abnormal ambulatory blood pressure monitoring (ABPM) represent two established modifiable risk factors associated with development of CKD. We performed a cross-sectional study of this cohort at baseline and identified that hyperuricemia and abnormal ABPM were associated with lower eGFR at baseline.1 This prospective study evaluated the annual change in estimated GFR (eGFR) among patients with and without hyperuricemia, nocturnal hypertension, and abnormal nocturnal dipping. As children with SCA experience a rise in eGFR in the first decade of life prior to a decline, we restricted this analysis to the change in eGFR from 10–18 years of age. We hypothesized that hyperuricemia and abnormal APBM would be associated with a decline in eGFR during the second decade of life. The IRB approved, UAB Pediatric Renal SCA cohort enrolled 192 pediatric participants to evaluate the impact of nocturnal hypertension and biomarkers of renal injury on progression of chronic kidney disease (NCT02373241). Participants with HbSS or HbSB0 thalassemia, ages six to 19 years, were eligible to enroll in the study for annual blood and urine studies of chronic kidney disease. Participants were given an option to complete a 24-hour ambulatory blood pressure monitoring (ABPM). We prospectively collected eGFR by cystatin C and uric acid levels at each annual standard of care sickle cell clinic visit; we also abstracted eGFR values retrospectively from annual standard of care clinic visits. Fifty-nine participants older than age 10 completed 24-hour ambulatory blood pressure. Annual decline in eGFR was the primary outcome for this analysis and our predictor variables were hyperuricemia and abnormal nocturnal blood pressure. Pediatric patients with sickle cell anemia experience an elevation in eGFR during the first decade of life, before a decline in eGFR during the second decade of life. For this study of decline in eGFR, we restricted our analysis to 132 SCA participants with eGFR values obtained between 10–18 years of age. We recorded a total of 642 cystatin based eGFR levels during annual SCA clinic well visits. We defined hyperuricemia as a mean uric acid level ≥ 5.5 mg/dL. Nocturnal hypertension was defined as >25% of nocturnal blood pressure (BP) readings >95th percentile. Abnormal nocturnal dipping was defined by a <0% decrease in BP while sleeping (BP increased while sleeping). Attenuated nocturnal dipping was defined by <10% to ≥0% dip in mean BP while sleeping. We defined normal blood pressure dipping by ≥10% dip in mean BP. To compare the change in GFR as a function of age for the different groups, we fitted a random intercept mixed model with age (linear), groups and age by group interaction. If the interaction was not significant, we refit the model with only the main effects of age and groups. We performed analyses using SASv9.4. The mean eGFR was 167 ± 34 mL/min/1.73 m2 with a mean age of 13.9 ± 2.6 years. We identified 39 (30%) participants with hyperuricemia and 93 (70%) without hyperuricemia. We found a significant interaction (P = .003) between age and hyperuricemia group implying that the change in eGFR over time depends on hyperuricemia. At age 10, we identified no significant difference between eGFR among groups. As the participants age, those with hyperuricemia showed a significant decrease in mean eGFR of −2.46 mL/min/1.73 m2/year (P = .002). (Figure 1(A)) In contrast, participants without hyperuricemia did not experience a significant change in mean eGFR over time (0.52 mL/min/1.73 m2/year; P = .4). The mean eGFR (n = 279) among 59 participants completing ABPM was 161 ± 33 mL/min/1.73 m2 with a mean age of 14.4 ± 2.5 years. Twenty (34%) participants demonstrated an increase in mean BP while sleeping (group one: abnormal nocturnal dipping). Twenty-five (42%) participants had a mean BP that decreased by 0%–10% while sleeping (group two: attenuated dipping). Fourteen (24%) participants had a mean BP that decreased by >10% while sleeping (group three: normal nocturnal dipping). We did not find a significant interaction between age and the ABPM group implying that there is no evidence that the changes in mean eGFR across the age are different among the three groups. However, we found a significant group effect (P = .04) for a fixed age. In particular, the mean eGFR is significantly lower among group one participants as compared to group two (−17.2 mL/min/1.73 m2, 95% CI: −32.9, −1.4; P = .033) and group three (−20.8 mL/min/1.73 m2, 95% CI: −39.0, −2.5; P = .026). We did not identify a difference in the mean eGFR between participants in groups two and three (P = .7) (Figure 1(B)). Twenty-four (41%) participants had nocturnal hypertension and 35 (59%) had normal nighttime blood pressure. We did not identify a significant change in eGFR over time among those with and without nocturnal hypertension (P = .43) (Figure 1(C)). Hyperuricemia is prevalent in pediatric and adult patients with SCA.1, 2 Hyperuricemia is a well-established independent risk factor associated with CKD in children; the Chronic Kidney Disease in Children study identified that children with hyperuricemia developed either a 30% decline in GFR or initiation of dialysis earlier than children without hyperuricemia.3 Cross-sectional pediatric SCA studies identified patients with hyperuricemia having a lower eGFR than patients without hyperuricemia.1, 2 This study provides important prospective data that hyperuricemia is associated with a more rapid decline in eGFR during adolescence. The mechanism of action of hyperuricemia on kidney disease is multifactorial. Hyperuricemia activates the renin-angiotensin-aldosterone system, endothelin, and suppresses nitric oxide. Increased intracellular urate stimulates NADPH oxidase, impairs mitochondrial function and activates inflammatory cytokines. These cellular and vascular effects results in elevated glomerular hydrostatic pressure and progressive glomerulopathy. The SCA patients with hyperuricemia also demonstrate an increase in cellular adhesion molecules, oxidative stress, hemolytic markers, and inflammatory cytokines which may further exacerbate kidney injury. Lowering uric acid to prevent progressive CKD has been studied in diabetes. Two recent large randomized trials in diabetes did not demonstrate a benefit to allopurinol for attenuating the decline in GFR.4, 5 While these results could suggest lowering uric acid will not impact progression to end-stage renal disease in SCA, several important points should be considered. First, these trials were conducted in participants with diabetes and CKD who were already receiving angiotensin blocking medications. As uric acid may stimulate the renin-angiotensin-aldosterone system, evaluating allopurinol in patients already receiving angiotensin blockade may minimize or eliminate the benefit of randomization to allopurinol. Second, patients in these randomized studies had long-standing CKD due to diabetes. It is postulated that hyperuricemia induces CKD through a two-step process; the first being dose responsive to serum uric acid and reversible and the second being irreversible and progressive even if uric acid is lowered. To date most clinical trials assessing urate lowering therapy have only studied patients expected to be in the second phase of disease progression. Additional research for uric acid lowering medications may prove beneficial if conducted earlier in life or prior to progression to persistent and higher stage kidney disease. A study of febuxostat also did not demonstrate an overall benefit to patients with stage three kidney disease, but did show a benefit in patients without proteinuria or better initial kidney function at baseline.6 Murine SCA models have demonstrated that hyperuricemia is associated with hemolysis and treatment with febuxostat improved the hemolytic phenotype..7 This association between uric acid and change and eGFR in SCA will need to be confirmed in a prospective randomized controlled trial of uric acid lowering medication. Forty to 70 percent of patients with SCA have abnormal ABPM.1, 8 Abnormal nocturnal BP dipping may be associated with kidney disease in SCA; however, adult data is likely required to support its impact on decline in eGFR over time. Abnormal ABPM is associated with CKD and cardiovascular events in non-SCA populations. As the prevalence of abnormal ABPM is high in SCA, additional research should be performed. This study provides important prospective data on change in eGFR during pediatrics; however, a few limitations are worth noting. First, individual eGFR values are subject to bias and imprecision. By using an average of 4.5 eGFR values per participant, we minimized imprecision. Second, we need adult data to determine if hyperuricemia and abnormal ABM are associated with end-stage renal disease. However, as mortality with end-stage renal disease is high and single nephron sclerotic injury occurs prior to a decline in GFR, we believe that identifying risk factors for eGFR decline and intervening during pediatrics will ensure a greater success in preventing mortality. Third, we did not evaluate SCA modifying therapy on outcomes. A prospective clinical study with strict adherence measurements can better determine the role of hydroxyurea or other SCA therapies on decline in GFR. This study provides important prospective data to support monitoring hyperuricemia in adolescent patients with SCA. Uric acid reducing medications including xanthine oxidase inhibitors have demonstrated efficacy in ameliorating the progression of CKD in non-SCA pediatric populations. While abnormal blood pressure dipping was associated with lower eGFR, it did not change the trajectory of eGFR decline with respect to age. However, as a risk factor for cardiovascular outcomes and mortality for other populations, clinicians could consider performing ABPM in higher risk patients. In conclusion, this data provides support for future randomized pilot studies of uricosuric agents in SCA patients with hyperuricemia to prevent progression of CKD. The authors acknowledge the participants and families that participated in this prospective cohort study. Jeffrey D. Lebensburger designed and performed the study, analyzed, and interpreted the results, and wrote the manuscript. Daniel I. Feig designed the study and interpreted the results. Inmaculada Aban analyzed and interpreted the results. Lee M Hilliard performed the study and interpreted the results. J.L. is on the advisory board for Novartis and received grant funding from Pfizer. This work is supported by the National Institutes of Health, National Heart, Lung, and Blood Institutes grant K23 HL127100 and the American Society of Hematology, ASH Scholars Award. We will ensure that data are shared in compliance with the NIH Data and Resource Sharing Policy. In compliance with this policy, data collected in this study will be made available to other researchers, after the goals have been met and primary aims have been published. Disclosure of sensitive health and behavior data presents a potential risk to human subjects, and we will take all steps to ensure that this does not happen when data are shared. Furthermore, all identifying information related to the individual participants will be removed when data are shared, and our study ID number will be replaced by a new ID number selected at random. In addition, we will strongly recommend that all recipient groups ensure that every member of the staff sign a Confidentiality Agreement. We will develop a data and resource sharing agreement with the legal advice from the Compliance Office of the University of Alabama at Birmingham, and ensure that we follow NIH guidelines with respect to data sharing. Before data are shared with researchers, we will require that researchers enter into a data-sharing and resource-sharing agreement. This agreement will ensure that: (a) data are used only for research purposes; (b) data do not identify any individual participant; (c) data are secure, using appropriate computer technology; and (d) there is a commitment to destroy or return data after analyses are completed.