Authors' Reply: A CrystalIndependent Role for Uric Acid in AKI Associated with Tumor Lysis Syndrome

We read with great interest the letter of Ejaz et al.1 who raise an important point that deserves to be further discussed concerning the mechanisms involved in tumor lysis syndrome (TLS)–induced AKI. In their letter, they highlight the multiple pathways connecting hyperuricemia in renal endothelial dysfunction and TLS-AKI. We totally agree with the authors that, beyond crystal-induced nephropathies, hyperuricemia may be responsible for noncrystal mediated AKI, as demonstrated in several experimental models, as well as human data. Indeed, uric acid has shown deleterious renal effects by inducing renal vasoconstriction and increasing renal oxidation and tissue inflammation. However, if some pilot studies have suggested that lowering uric acid levels with recombinant urate oxidase (rasburicase) may improve GFRs in TLS patients, this was not confirmed in controlled randomized studies. Indeed, studies that have compared allopurinol and rasburicase showed that rasburicase provided control of uric acid levels more rapidly than allopurinol, but with no demonstrated benefit on the incidence of AKI.2 In a large meta-analysis including randomized controlled trials and controlled clinical trials of rasburicase for the prevention or treatment of TLS, Cheuk et al.3 demonstrated that the impact of rasburicase on clinical TLS, AKI, and mortality is still unclear. Moreover, Darmon et al.4 have shown that AKI is still prevalent during TLS (28% of the patients) despite the wide use of rasburicase. In fact, this fraction of patients with AKI is similar to those of previous studies of TLS performed before the rasburicase era, with AKI occurring in up to one-third of patients with TLS. In our study, as noted by Ejaz et al., median serum uric acid levels in patients with TLS, TLS-AKI, and non-AKI TLS were 497 mmol/L, 520 mmol/L, and 404 mmol/L, respectively, at admission, before rasburicase administration. However, as shown in Table 2 in the study, rasburicase was administered in 83.6%, 82.6%, and 88.9%, respectively, of the patients, with a median delay <1 day after admission.5 Rasburicase is known to be highly effective in decreasing uric acid levels, with a mean reduction of acid uric concentrations of 88% within 4 hours.2 To fully address the issue raised by the authors, we looked at uric acid levels at 12 hours, 24 hours, and 48 hours after admission in our cohort and found that uric acid concentrations were drastically decreased at each of these time points in patients with TLS, TLS-AKI, and non-AKI TLS (Table 1). These data confirm that rasburicase was efficient in promptly lowering uric acid levels. Table 1. - Kinetic of uric acid levels in patients with TLS Uric acid levels at different time points TLS (N=55) TLS-AKI (N=46) Non-AKI TLS (N=9) Uric acid (mmol/L) at admission, median (25–75) 497.0 (226.0–615.0) 520.0 (270.5–696.5) 404.0 (220.9–511.3) Uric acid (mmol/L) at 12 h, median (25–75) 123.7 (48.3–681.0) 127.4 (49.0–681.0) 120.0 (28.0–536.0) Uric acid (mmol/L) at 24 h, median (25–75) 94.0 (55.2–626.0) 92.5 (54.8–626.0) 96.0 (86.0–461.0) Uric acid (mmol/L) at 48 h, median (25–75) 91.0 (63.0–878.0) 89.5 (60.0–878.0) 91.0 (77.0–325.0) TLS, tumor lysis syndrome. Although these data do not rule out a contribution of initial hyperuricemia in AKI during TLS, especially at the initial stage of AKI development, it suggests that other mechanisms are involved in TLS-induced AKI. More experimental and clinical data are needed to evaluate the exact role of hyperuricemia in organ failures in patients with TLS.