Studies have demonstrated the presence of a strong association between serum uric acid (SUA) and acute kidney injury (AKI) consistently across several disease models. Exposure to SUA at different time periods and concentrations has reliably resulted in AKI whether assessed by conventional or novel biomarkers or by kinetic estimated glomerular filtration rate (KeGFR) engineered for non-steady dynamic states. In experimental models, moderate hyperuricemia was associated with an absence of intrarenal crystals, manifestation of tubular injury, macrophage infiltration, and increased expression of inflammatory mediators that were attenuated with uric acid lowering therapy with rasburicase, a recombinant urate oxidase. In a pilot clinical trial, treatment with rasburicase was associated with a decreased incidence of AKI and evidence for less renal structural injury. Lowering SUA also improved KeGFR and estimated glomerular filtration rate in 2 separate studies. SUA has also been linked to diabetic nephropathy, hypertension, cardiovascular disease, chronic kidney disease, metabolic syndrome, and their mechanisms of action share many common traits. In this article, we explore the evidence for the causal role of SUA in AKI using Bradford Hill criteria as a guideline with data integration from related fields.

Background: The aim of the study was to investigate the effects of serum uric acid (SUA) on acute kidney injury (AKI) in patients undergoing cardiac surgery. Methods: Prospectively collected data from a previous study were analyzed to investigate the relationship between SUA and AKI as assessed by neutrophil gelatinase-associated lipocalin (NGAL), serum creatinine (SCr) and kinetic estimated glomerular filtration rate (KeGFR). Results: Patients undergoing cardiovascular surgery (n = 37) were included. SUA was measured at postoperative 1 h. Statistically significant correlations were present between SUA and NGAL measured at postoperative 1 h (r = 0.39, p = 0.008), 6 h (r = 0.31, p = 0.029) and 24 h (r = 0.31, p < 0.001), respectively. Significant correlations were also noted between SUA and SCr measured on postoperative day 1 (r = 0.41, p = 0.006), day 2 (r = 0.29, p = 0.042) and day 3 (r = 0.42, p = 0.009). Negative correlations were demonstrated between SUA and day 1 (r = -0.44, p = 0.007), day 2 (r = -0.43, p = 0.007), day 3 (r = -0.44, p = 0.006 and day 4 KeGFR (r = -0.35, p = 0.035). The inverse relationship of SUA and KeGFR was also demonstrated with a different method (Jelliffe) of measurement. Conclusions: A reduction in glomerular filtration rate (GFR) can lead to a rise in SUA. However, in this study, we are able to show that SUA at 1 h (maximal dilution time) effectively predicts subsequent changes in urinary NGAL, SCr, KeGFR, and the development of AKI. Thus, these findings suggest that uric acid precedes and predicts acute changes in renal function and cannot be ascribed to a simple relationship in which a reduced GFR raises SUA.

Background: In this study, we investigated the relationship between serum uric acid (SUA) and renal function in a unique patient cohort wherein SUA levels fluctuate during the course of standard care. Methods: Correlation coefficients between SUA and serum creatinine (SCr) and kinetic estimated GFR (KeGFR) were retrospectively investigated in acute myeloid leukemia (AML) patients, and statistically significant and clinically relevant determinants were studied in multiple regression models. Results: One hundred and twenty-six patients were included in the analysis. Baseline SUA was associated with an increased risk for acute kidney injury (AKI; OR 1.27, 95% CI 1.1-1.5, p = 0.003) and laboratory tumor lysis syndrome (OR 1.26, 95% CI 1.1-1.5, p = 0.005). Prophylactic uric acid-lowering therapy and hydration resulted in lower SUA values from baseline in 88.1% of the patients, the lowest values were observed on post-induction day 1 (20.4% reduction). Significant linear correlations were observed between SUA and SCr (r = 0.35, p < 0.001) values with a significant inverse correlation between SUA and KeGFR on day 1 (r = -0.33, p < 0.001) that persisted through day 4. By subgroup analysis, patients with primary AML (r = -0.49, p < 0.001), baseline SUA >5.5 mg/dl (r = -0.41, p = 0.002) and baseline eGFR >60 ml/min/1.73 m² (r = -0.51, p < 0.001) demonstrated robust relationships between SUA and KeGFR. The relationship was more robust when the groups were combined (primary AML plus baseline SUA >5.5 mg/dl plus baseline eGFR >60 ml/min/1.73 m², r = -0.52, p < 0.001). Conclusion: The demonstration of linear relationship between SUA and SCr and inverse relationship between SUA and KeGFR reinforces the emerging translational physiological evidence regarding the role of uric acid in AKI.

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We report the case of a 48-year-old man with acquired Fanconi syndrome due to IgG-kappa monoclonal gammopathy, who received a single dose of denosumab 60 mg for secondary prevention of skeletal fractures, in conjunction with oral calcium and vitamin D supplementation. The treatment was complicated with a severe, symptomatic hypocalcemia occurring 1 month after the injection and necessitating 4 weeks of intravenous calcium gluconate therapy. Similarly to bisphosphonates, inhibitors of the receptor activator of nuclear factor kappa-B ligand may not be appropriate for the treatment of acquired Fanconi syndrome and other forms of osteomalacia regardless of the degree of renal insufficiency and vitamin D levels. Clinicians should carefully interpret the radiographic and bone densitometry results in light of diverse mechanisms of bone demineralization and potential dependence of calcium homeostasis on high bone turnover.