A Crystal-Independent Role for Uric Acid in AKI Associated with Tumor Lysis Syndrome

Arnaud et al.¹ make the important finding that AKI in tumor lysis syndrome (TLS) may occur in the absence of crystals, suggesting that other mechanisms may contribute to kidney damage besides the well-established mechanisms resulting from urate crystalluria with intratubular crystal precipitation. While these authors provide tantalizing evidence that extracellular histones may contribute to AKI by causing endothelial injury, we would also like to note that hyperuricemia in the absence of crystal deposition can also cause endothelial dysfunction, inflammation with the activation of inflammasomes, renal vasoconstriction, and reduced renal blood flow and GFR. In the cisplatin model of renal injury, hyperuricemia in the absence of crystal deposition exacerbated the renal injury, leading to local inflammation and worse kidney function.² Modest elevations in serum uric acid have also been found to predict AKI from numerous causes, including after contrast administration, after cardiovascular surgery, and in TLS.³ Uric acid demonstrated linear correlation with serum creatinine and inverse correlation with kinetic eGFR in several clinical models. Pilot clinical trials suggest that lowering uric acid in subjects with mild to moderate hyperuricemia can reduce AKI (biomarkers) following cardiovascular surgery.⁴ In TLS, lowering uric acid attenuated rise in serum creatinine, decreased the incidence of AKI, and improved GFR. In a meta-analysis of 11 studies, treatment with allopurinol was associated with a significant increase in endothelium-dependent vasodilatation (even in asymptomatic patients with normal renal function), decrease in serum creatinine, and improvement in GFR.

In the current study, serum uric acid levels in patients with TLS, TLS-AKI, and non-AKI TLS were 8.36 mg/dl, 8.74 mg/dl, and 6.79 mg/dl, respectively. However, the majority of patients with AKI did not have crystalluria. There were no crystal deposits in TLS mice due to the presence of uricase in the mice liver that degrades uric acid into allantoin. These observations are consistent with a crystal independent role for uric acid in AKI. More studies need to evaluate noncrystalline drives of AKI in TLS. New detective work suggests that extracellular histones represent some of the criminals. We would suggest that soluble uric acid is also an accomplice. We recommend more studies to investigate the role of urate lowering therapy in AKI.

Disclosures

R.J. Johnson has equity with XORT Therapeutics, which is developing novel xanthine oxidase inhibitors, is an inventor on several patents on the role of uric acid in hypertension, metabolic syndrome, and diabetic nephropathy that resulted from research (US Patent Nos. 7,799,794; 8,236,488; 8,557,831; 9,155,740 B), and has consulted for AstraZeneca, Danone Research Foundation, and Horizon Pharmaceuticals. R.J. Johnson also reports Ownership Interest: Colorado Research Partners LLC (founder shares); Research Funding: NIH, Veteran's Administration; Honoraria: Horizon Pharmaceutical, Universities; Patents or Royalties: Comprehensive Clinical Nephrology (Elsevier) and Nature Wants Us to Be Fat (BenBella). T. Beaver reports Consultancy: Jace orthopedics; Ownership Interest: Rivian, Lucid, Shockwave, Exxon, Carnival, Norwegian, Disney, Genuine Parts, Amazon; Research Funding: Surgical Site PI for valve trials, Edwards, Medtronic, Abbot; and Advisory or Leadership Role: Atricure Inc Scientific Advisory for IST trial. All remaining authors have nothing to disclose.

Funding

None.

Author Contributions

A.A. Ejaz conceptualized the study and was responsible for data curation; T.M. Beaver, A.A. Ejaz, R.J. Johnson, and R. Mohandas were responsible for formal analysis; T.M. Beaver, A.A. Ejaz, and R. Mohandas were responsible for investigation; T.M. Beaver, R. Johnson, and R. Mohandas were responsible for methodology; A.A. Ejaz and R.J. Johnson wrote the original draft; and T.M. Beaver, A.A. Ejaz, R.J. Johnson, and R. Mohandas reviewed and edited the manuscript.