Uric acid lowering for slowing CKD progression after the CKD-FIX trial: a solved question or still a dilemma?

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ABSTRACT

Hyperuricemia has been associated with several cardiovascular risk factors and is a well-known predictor of kidney disease. In vitro studies as well as animal models highlighted a role for uric acid in the development and progression of haemodynamic and tissue damage at the renal level leading to glomerular and tubulointerstitial abnormalities. Urate-lowering treatment, especially by xanthine oxidase inhibitors, has been proposed in order to improve kidney outcomes. However, recent randomized controlled trials failed to demonstrate a beneficial effect of allopurinol or febuxostat on renal disease, casting doubts on the role of this therapeutical approach to improve nephroprotection. We provide a critical overview of current literature on this topic and offer a possible interpretation of results from recent intervention trials with urate-lowering treatment on renal outcomes.

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Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.

Marian Goicoechea, Soledad García de Vinuesa, Ursula Verdalles … (2010)

Hyperuricemia is associated with hypertension, inflammation, renal disease progression, and cardiovascular disease. However, no data are available regarding the effect of allopurinol in patients with chronic kidney disease. We conducted a prospective, randomized trial of 113 patients with estimated GFR (eGFR) <60 ml/min. Patients were randomly assigned to treatment with allopurinol 100 mg/d (n = 57) or to continue the usual therapy (n = 56). Clinical, biochemical, and inflammatory parameters were measured at baseline and at 6, 12, and 24 months of treatment. The objectives of study were: (1) renal disease progression; (2) cardiovascular events; and (3) hospitalizations of any causes. Serum uric acid and C-reactive protein levels were significantly decreased in subjects treated with allopurinol. In the control group, eGFR decreased 3.3 +/- 1.2 ml/min per 1.73 m(2), and in the allopurinol group, eGFR increased 1.3 +/- 1.3 ml/min per 1.73 m(2) after 24 months. Allopurinol treatment slowed down renal disease progression independently of age, gender, diabetes, C-reactive protein, albuminuria, and renin-angiotensin system blockers use. After a mean follow-up time of 23.4 +/- 7.8 months, 22 patients suffered a cardiovascular event. Diabetes mellitus, previous coronary heart disease, and C-reactive protein levels increased cardiovascular risk. Allopurinol treatment reduces risk of cardiovascular events in 71% compared with standard therapy. Allopurinol decreases C-reactive protein and slows down the progression of renal disease in patients with chronic kidney disease. In addition, allopurinol reduces cardiovascular and hospitalization risk in these subjects.

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Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level.

Yui-Pong Siu, Kay-Tai Leung, Matthew Tong … (2006)

Hyperuricemia is associated strongly with the development of hypertension, renal disease, and progression. Allopurinol decreases serum uric acid levels by inhibiting the enzyme xanthine oxidase. We hypothesized that administrating allopurinol to decrease serum uric acid levels to the normal range in hyperuricemic patients with chronic kidney disease may be of benefit in decreasing blood pressure and slowing the rate of renal disease progression in these patients. We conducted a prospective, randomized, controlled trial of 54 hyperuricemic patients with chronic kidney disease. Patients were randomly assigned to treatment with allopurinol, 100 to 300 mg/d, or to continue the usual therapy for 12 months. Clinical, hematologic, and biochemical parameters were measured at baseline and 3, 6, and 12 months of treatment. We define our study end points as: (1) stable kidney function with less than 40% increase in serum creatinine level, (2) impaired renal function with creatinine level increase greater than 40% of baseline value, (3) initiation of dialysis therapy, and (4) death. One patient in the treatment group dropped out because of skin allergy to allopurinol. Serum uric acid levels were significantly decreased in subjects treated with allopurinol, from 9.75 +/- 1.18 mg/dL (0.58 +/- 0.07 mmol/L) to 5.88 +/- 1.01 mg/dL (0.35 +/- 0.06 mmol/L; P < 0.001). There were no significant differences in systolic or diastolic blood pressure at the end of the study comparing the 2 groups. There was a trend toward a lower serum creatinine level in the treatment group compared with controls after 12 months of therapy, although it did not reach statistical significance (P = 0.08). Overall, 4 of 25 patients (16%) in the allopurinol group reached the combined end points of significant deterioration in renal function and dialysis dependence compared with 12 of 26 patients (46.1%) in the control group (P = 0.015). Allopurinol therapy significantly decreases serum uric acid levels in hyperuricemic patients with mild to moderate chronic kidney disease. Its use is safe and helps preserve kidney function during 12 months of therapy compared with controls. Results of this study need to be confirmed with an additional prospective trial involving a larger cohort of patients to determine the long-term efficacy of allopurinol therapy and in specific chronic kidney disease subpopulations.

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Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2.

John Kanellis, Susumu Watanabe, Jin Li … (2003)

Previous studies have reported that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation in vitro. We hypothesized that uric acid may also have direct proinflammatory effects on VSMCs. Crystal- and endotoxin-free uric acid was found to increase VSMC monocyte chemoattractant protein-1 (MCP-1) expression in a time- and dose-dependent manner, peaking at 24 hours. Increased mRNA and protein expression occurred as early as 3 hours after uric acid incubation and was partially dependent on posttranscriptional modification of MCP-1 mRNA. In addition, uric acid activated the transcription factors nuclear factor-kappaB and activator protein-1, as well as the MAPK signaling molecules ERK p44/42 and p38, and increased cyclooxygenase-2 (COX-2) mRNA expression. Inhibition of p38 (with SB 203580), ERK 44/42 (with UO126 or PD 98059), or COX-2 (with NS398) each significantly suppressed uric acid-induced MCP-1 expression at 24 hours, implicating these pathways in the response to uric acid. The ability of both n-acetyl-cysteine and diphenyleneionium (antioxidants) to inhibit uric acid-induced MCP-1 production suggested involvement of intracellular redox pathways. Uric acid regulates critical proinflammatory pathways in VSMCs, suggesting it may have a role in the vascular changes associated with hypertension and vascular disease.

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Author and article information

Contributors

Giovanna Leoncini:

ORCID: https://orcid.org/0000-0001-7539-9464

Cecilia Barnini

Luca Manco

Giulia Nobili

Daniele Dotta

Martina Penso

Elisa Russo:

ORCID: https://orcid.org/0000-0003-1279-3178

Francesca Cappadona

Francesca Viazzi:

ORCID: https://orcid.org/0000-0003-4219-7043

Roberto Pontremoli:

ORCID: https://orcid.org/0000-0003-1238-872X

Journal

Journal ID (nlm-ta): Clin Kidney J

Journal ID (iso-abbrev): Clin Kidney J

Journal ID (publisher-id): ckj

Title: Clinical Kidney Journal

Publisher: Oxford University Press

ISSN (Print): 2048-8505

ISSN (Electronic): 2048-8513

Publication date Collection: September 2022

Publication date (Electronic): 12 March 2022

Publication date PMC-release: 12 March 2022

Volume: 15

Issue: 9

Pages: 1666-1674

Affiliations

Department of Internal Medicine, University of Genoa and IRCCS Ospedale Policlinico San Martino , Genova, Italy

Author notes

Correspondence to: Roberto Pontremoli; E-mail: roberto.pontremoli@ 123456unige.it

Author information

Giovanna Leoncini https://orcid.org/0000-0001-7539-9464

Elisa Russo https://orcid.org/0000-0003-1279-3178

Francesca Viazzi https://orcid.org/0000-0003-4219-7043

Roberto Pontremoli https://orcid.org/0000-0003-1238-872X

Article

Publisher ID: sfac075

DOI: 10.1093/ckj/sfac075

PMC ID: 9394710

PubMed ID: 36003668

SO-VID: a7a656bb-7f88-4494-b94c-73d68fc552b7

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

History

Date received : 23 December 2021

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Pages: 9

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Uric acid lowering for slowing CKD progression after the CKD-FIX trial: a solved question or still a dilemma?

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Karger: Nephrology

Most cited references 52

Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.

Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level.

Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2.

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Cited by 5

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