A Case of Acute Kidney Injury in a Patient with Renal Hypouricemia without Intense Exercise

Aomura, Daiki; Sonoda, Kosuke; Harada, Makoto; Hashimoto, Koji; Kamijo, Yuji

doi:10.1159/000506673

Cited by 7 publications

(7 citation statements)

References 14 publications

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“…With novel Urat1 - Uox DKO mice we observed an elevation in the level of plasma Cr and BUN and a decrease of CL Cr after the forced swimming test, whereas no such fluctuation in these renal damage parameters was observed with Uox -KO mice (Figure 2, A–C). Indeed, in clinical cases it has been reported that EIAKI of RHUC1 resulted in increased serum Cr and BUN as renal damage markers 25 – 29 . Thus, our results suggest that novel Urat1 - Uox DKO mice induce EIAKI similar to that observed for RHUC1 patients.…”

Section: Discussionsupporting

confidence: 81%

“…Indeed, in clinical cases it has been reported that EIAKI of RHUC1 resulted in increased serum Cr and BUN as renal damage markers. [25][26][27][28][29] Thus, our results suggest that novel Urat1-Uox DKO mice induce EIAKI similar to that observed for RHUC1 patients. In addition, Urat1-Uox DKO mice had elevated plasma UA, urinary UA/Cr ratio, and FE UA after exercise (Figure 2, D-F).…”

Section: Discussionsupporting

confidence: 81%

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Xanthine Oxidoreductase Inhibitors Suppress the Onset of Exercise-Induced AKI in High HPRT Activity Urat1-Uox Double Knockout Mice

Hosoya¹,

Uchida²,

Shibata³

et al. 2022

JASN

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Background Hereditary renal hypouricemia type-1 (RHUC1) is caused by URAT1/SLC22A12 dysfunction, resulting in urolithiasis and exercise-induced acute kidney injury (EIAKI). Because, however, there is no useful experimental RHUC1 animal model, the precise pathophysiological mechanisms underlying EIAKI have yet to be elucidated. We established a high HPRT activity Urat1-Uox double knockout (DKO) mouse as a novel RHUC1 animal model for investigating the cause of EIAKI as well as the potential therapeutic effect of xanthine oxidoreductase inhibitors (XOIs). Methods The novel Urat1-Uox DKO mice were used in a forced swimming test as loading exercise to explore the onset mechanism of EIAKI and evaluate related purine metabolism and renal injury parameters. ResultsUrat1-Uox DKO mice had uricosuric effects and elevated levels of plasma creatinine (Cr) and blood urea nitrogen (BUN) as renal injury markers, and decreased Cr clearance (CLCr) observed in a forced swimming test. In addition, Urat1-Uox DKO mice had increased NLRP3 inflammasome activity and downregulated levels of Na+-K+-ATPase (NKA) protein in the kidney, as Western blot analysis showed. Finally, we demonstrated that topiroxostat and allopurinol, XOIs, improved renal injury and functional parameters of EIAKI. ConclusionsUrat1-Uox DKO mice are a useful experimental animal model for human RHUC1. The pathogenic mechanism of EIAKI was found to be due to increased levels of IL-1β via NLRP3 inflammasome signaling and NKA dysfunction associated with excessive urinary UA excretion. In addition, XOIs appear to be a promising therapeutic agent for the treatment of EIAKI.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 81%

Xanthine Oxidoreductase Inhibitors Suppress the Onset of Exercise-Induced AKI in High HPRT Activity Urat1-Uox Double Knockout Mice

Hosoya¹,

Uchida²,

Shibata³

et al. 2022

JASN

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“…According to local availability and confidence in interpreting the results, direct genotyping with Sanger sequencing can even be considered as an early-option diagnostic tool to provide rapid genetic results and a definitive diagnosis of the disease. Of note, Sanger sequencing failed to identify pathogenic variants in three patients (8%) with a clinical picture of RHUC-AKI included in our cohort analysis [ 10 , 11 ]. In the future, MPS could be considered in order to identify additional genes involved in the pathogenesis of RHUC and to perform reliable genotype–phenotype correlations.…”

Section: Discussionmentioning

confidence: 99%

Clinical features suggesting renal hypouricemia as the cause of acute kidney injury: a case report and review of the literature

et al. 2022

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Hypouricemia is defined as a level of serum uric acid below 2 mg/dl. Renal hypouricemia is related to genetic defects of the uric acid tubular transporters urate transporter 1 and glucose transporter 9. Patients with renal hypouricemia can be completely asymptomatic or can develop uric acid kidney stones or acute kidney injury, particularly after exercise. Renal hypouricemia is especially challenging to diagnose in patients with acute kidney injury, due to the nonspecific clinical, hematochemical and histological features. No common features are reported in the literature that could help clinicians identify renal hypouricemia-acute kidney injury. Currently available guidelines on diagnosis and management of renal hypouricemia provide limited support in defining clues for the differential diagnosis of renal hypouricemia, which is usually suspected when hypouricemia is found in asymptomatic patients. In this paper we report a case of renal hypouricemia-acute kidney injury developing after exercise. We carried out a review of the literature spanning from the first clinical description of renal hypouricemia in 1974 until 2022. We selected a series of clinical features suggesting a diagnosis of renal hypouricemia-acute kidney injury. This may help clinicians to suspect renal hypouricemia in patients with acute kidney injury and to avoid invasive, costly and inconclusive exams such as renal biopsy. Considering the excellent outcome of the patients reported in the literature, we suggest a “wait-and-see” approach with supportive therapy and confirmation of the disease via genetic testing.

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“…RHUC are known to be at risk for EIAKI, although RHUC may be asymptomatic except for hypouricemia [ 25 ]. It has been suggested that oxidative stress in RHUC subjects causes vasoconstriction and renal ischemia due to low blood UA, a scavenger of reactive oxygen species [ 36 ], or that high levels of UA crystallize in the renal tubules [ 11 ]. However, these hypotheses are contradictory and still controversial because EIAKI has not been reported in XU, which causes more severe hypouricemia than RHUC, and renal biopsy results of EIAKI in RHUC show few findings of UA precipitation in the renal tubular lumen or obstructive mechanisms [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Analysis of Purine Metabolism to Elucidate the Pathogenesis of Acute Kidney Injury in Renal Hypouricemia

Miyamoto

Sato²,

Nagata³

et al. 2022

Biomedicines

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Renal hypouricemia is a disease caused by the dysfunction of renal urate transporters. This disease is known to cause exercise-induced acute kidney injury, but its mechanism has not yet been established. To analyze the mechanism by which hypouricemia causes renal failure, we conducted a semi-ischemic forearm exercise stress test to mimic exercise conditions in five healthy subjects, six patients with renal hypouricemia, and one patient with xanthinuria and analyzed the changes in purine metabolites. The results showed that the subjects with renal hypouricemia had significantly lower blood hypoxanthine levels and increased urinary hypoxanthine excretion after exercise than healthy subjects. Oxidative stress markers did not differ between healthy subjects and hypouricemic subjects before and after exercise, and no effect of uric acid as a radical scavenger was observed. As hypoxanthine is a precursor for adenosine triphosphate (ATP) production via the salvage pathway, loss of hypoxanthine after exercise in patients with renal hypouricemia may cause ATP loss in the renal tubules and consequent tissue damage.

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A Case of Acute Kidney Injury in a Patient with Renal Hypouricemia without Intense Exercise

Cited by 7 publications

References 14 publications

Xanthine Oxidoreductase Inhibitors Suppress the Onset of Exercise-Induced AKI in High HPRT Activity Urat1-Uox Double Knockout Mice

Xanthine Oxidoreductase Inhibitors Suppress the Onset of Exercise-Induced AKI in High HPRT Activity Urat1-Uox Double Knockout Mice

Clinical features suggesting renal hypouricemia as the cause of acute kidney injury: a case report and review of the literature

Analysis of Purine Metabolism to Elucidate the Pathogenesis of Acute Kidney Injury in Renal Hypouricemia

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