Effects of Allopurinol on the Progression of Chronic Kidney Disease

Badve, Sunil V.; Pascoe, Elaine M.; Tiku, Anushree; Boudville, Neil; Brown, Fiona G.; Cass, Alan; Clarke, Philip; Dalbeth, Nicola; Day, Richard O.; Zoysa, Janak R de; Douglas, Bettina; Faull, Randall J.; Harris, David C.H.; Hawley, Carmel M.; Jones, Graham; Kanellis, John; Palmer, Suetonia C.; Perkovic, Vlado; Rangan, Gopala K.; Reidlinger, Donna; Robison, Laura; Walker, Robert; Walters, Giles; Johnson, David W.; Investigators, Ckd-Fix Study

doi:10.1056/nejmoa1915833

Cited by 308 publications

(245 citation statements)

References 25 publications

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“…Therefore, XO inhibitors have potential for use as therapeutic drugs that reduce oxidative stress [ 15 ]. However, the XO inhibitor allopurinol does not inhibit renal dysfunction in patients with chronic kidney disease (CKD) and high risk of progression [ 16 ].Thus, the effect of XO inhibitors in terms of kidney protection remains controversial.…”

Section: Introductionmentioning

confidence: 99%

The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia

Kim

Ahn

et al. 2020

IJMS

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In the present study, we investigated the effects of xanthine oxidase (XO) inhibition on cholesterol-induced renal dysfunction in chronic kidney disease (CKD) mice, and in low-density lipoprotein (LDL)-treated human kidney proximal tubule epithelial (HK-2) cells. ApoE knockout (KO) mice underwent uninephrectomy to induce CKD, and were fed a normal diet or high-cholesterol (HC) diet along with the XO inhibitor topiroxostat (1 mg/kg/day). HK-2 cells were treated with LDL (200 µg/mL) and topiroxostat (5 µM) or small interfering RNA against xanthine dehydrogenase (siXDH; 20 nM). In uninephrectomized ApoE KO mice, the HC diet increased cholesterol accumulation, oxidative stress, XO activity, and kidney damage, while topiroxostat attenuated the hypercholesterolemia-associated renal dysfunction. The HC diet induced cholesterol accumulation by regulating the expressions of genes involved in cholesterol efflux (Nr1h3 and Abca1) and synthesis (Srebf2 and Hmgcr), which was reversed by topiroxostat. Topiroxostat suppressed the expressions of genes related to hypercholesterolemia-associated inflammation and fibrosis in the unilateral kidney. LDL stimulation evoked changes in the cholesterol metabolism, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and NF-κB pathways in HK-2 cells, which were mitigated by XO inhibition with topiroxostat or siXDH. These findings suggest that XO inhibition exerts renoprotective effects against hypercholesterolemia-associated kidney injury. XO could be a novel therapeutic target for hypercholesterolemia-associated kidney injury in uninephrectomized patients.

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Section: Introductionmentioning

confidence: 99%

The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia

Kim

Ahn

et al. 2020

IJMS

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“…Furthermore, the CKD-FIX trial has recently reported showing no benefit of allopurinol on cardiovascular or renal outcomes in advanced CKD compared to placebo. 35 In addition to the limitations discussed above, the population in this study was not ethnically diverse; allopurinol may have been less well tolerated in a group of patients with a different gene pool, 36 and in a more diverse trial population, the effect of the 300 mg dose may have been different. In addition, although regression of absolute myocardial mass is an important therapeutic target, this trial was not designed to quantify any change in character of myocardial tissue associated with allopurinol.…”

Section: Discussionmentioning

confidence: 94%

A Randomized, Controlled Trial of the Effect of Allopurinol on Left Ventricular Mass Index in Hemodialysis Patients

Rutherford

Ireland

Mangion

et al. 2021

Kidney International Reports

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“…151 Similarly, CKD-FIX (Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase) concluded that allopurinol treatment does not prevent renal function deterioration in patients with stage 3-4 chronic kidney disease and a high risk of progression to end-stage renal disease. 152 Interestingly, hyperuricemia was not an inclusion criterion in either of these 2 trials, yet most patients in both studies had baseline serum urate levels above the normality threshold (6.1 AE 1.5 mg/dl in PERL and 8.2 AE 1.8 mg/dl in CKD-FIX).…”

Section: Treatmentmentioning

confidence: 99%

Hyperuricemia as a trigger of immune response in hypertension and chronic kidney disease

Ponticelli

Podestà

Moroni

2020

Kidney International

100

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Effects of Allopurinol on the Progression of Chronic Kidney Disease

Cited by 308 publications

References 25 publications

The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia

The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia

A Randomized, Controlled Trial of the Effect of Allopurinol on Left Ventricular Mass Index in Hemodialysis Patients

Hyperuricemia as a trigger of immune response in hypertension and chronic kidney disease

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