The Role of Uric Acid in Kidney Fibrosis: Experimental Evidences for the Causal Relationship

Kim, Il Young; Lee, Jun Young; Lee, Soo Bong; Kwak, Ihm Soo

doi:10.1155/2014/638732

Cited by 62 publications

(56 citation statements)

References 83 publications

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“…The precipitation of urate in renal tubules may cause “uric acid nephropathy” [54]. Besides, the crystallization of the UA in the renal medullary interstitium can induce secretion of IL-1β, which may recruit more inflammatory cells and cause chronic interstitial inflammation and fibrosis [55–59]. Hyperuricemia may also induce proliferation of vascular smooth muscle cells and increase COX-2 expression and renal renin, leading to arteriopathy and hypertension–which may further aggravate kidney function[55].…”

Section: Discussionmentioning

confidence: 99%

Serum Uric Acid and Progression of Kidney Disease: A Longitudinal Analysis and Mini-Review

Tsai¹,

Lin²,

Kuo³

et al. 2017

PLoS ONE

148

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BackgroundIncreasing evidence supports the association between hyperuricemia and incident chronic kidney disease (CKD); however, there are conflicting data regarding the role of hyperuricemia in the progression of CKD. This study retrospectively assessed the longitudinal association between uric acid (UA) level and CKD progression in a Chinese population lived in Taiwan.MethodsPatients with physician diagnosis of hyperuricemia or receiving urate-lowering therapy between 2003 and 2005 were identified in the electronic medical records (EMR) of a tertiary medical center and were followed up until December 31, 2011. Patients were divided into four UA categories at the cut-off 6, 8, and 10 mg/dL. CKD progression was estimated by the change of estimated glomerular filtration rate (eGFR) in the linear mixed models. Kidney failure was defined as an eGFR less than 15 mL/min/1.73 m2 or requiring renal replacement therapy.ResultsA total of 739 patients were analyzed. In the full-adjusted model, patients with a baseline UA level ≥6 mg/dL had greater decline in eGFR ((β = -9.6, 95% CI -16.1, -3.1), comparing to those with a UA level less than 6 mg/dL. When stratifying patients into four UA categories, all three hyperuricemia categories (UA6-8, 8–10, ≥10 mg/dL) associated with a greater decline in eGFR over the follow-up period with an increasing dose-response, comparing to the lowest UA category. The risk of progression to renal failure increased 7% (hazard ratio 1.07, 95% CI 1.00, 1.14) for each 1mg/dL increase in baseline UA level. The influences of hyperuricemia on eGFR decline and the risk of kidney failure were more prominent in patients without proteinuria than those with proteinuria.ConclusionOur study showed a higher uric acid level is associated with a significant rapid decline in eGFR and a higher risk of kidney failure, particularly in patients without proteinuria. Our findings suggest hyperuricemia is a potential modifiable factor of CKD progression.

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Section: Discussionmentioning

confidence: 99%

Serum Uric Acid and Progression of Kidney Disease: A Longitudinal Analysis and Mini-Review

Tsai¹,

Lin²,

Kuo³

et al. 2017

PLoS ONE

148

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“…In several small controlled studies, lowering sUA reduced systemic inflammation [67][68][69][70][71][72]; however, larger trials are needed to confirm these results.…”

Section: Pathophysiological Aspectsmentioning

confidence: 99%

Serum uric acid and the risk of cardiovascular and renal disease

Borghi

Rosei

Bardin³

et al. 2015

Journal of Hypertension

427

277

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Substantial evidence suggests that chronic hyperuricemia is an independent risk factor for hypertension, metabolic syndrome, chronic kidney disease (CKD) and cardiovascular diseases. This highlights the need for greater attention to serum uric acid levels when profiling patients, and suggests that the threshold above which uricemia is considered abnormal is 6 mg/dl, in light of the available evidence. Another important question is whether lowering serum uric acid can improve cardiovascular and renal outcomes, and what therapeutic mechanism of action could provide more clinical benefits to patients; the available literature shows a trend toward improvement associated with administration of urate-lowering drugs, in particular for the xanthine oxidase inhibitors. The demonstrated efficacy of urate-lowering therapy on outcomes other than gout flares leads to the consideration that treatment may be beneficial even in the absence of overt gout when hyperuricemia accompanies other clinical conditions, such as urate deposition, advanced CKD or cardiovascular risk factors.

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“…At near neutral physiological pH, uric acid exists almost entirely as the urate anion, but in high concentration at low pH, uric acid is prone to form the crystals characteristic of nephrolithiasis and gout. [28][29][30] Many different pathways of increased production and/or reduced elimination of uric acid can account for elevated serum uric acid, as reviewed elsewhere, 23,24 but it is relevant to note, in the context of type 2 diabetes, that uric acid production is increased by a diet high in fructose (corn syrup). [25][26][27] Elevated uric acid concentrations are also associated with renal tubulo-interstitial fibrosis and chronic kidney disease (CKD).…”

Section: Sglt2 Inhibitors and Uric Acidmentioning

confidence: 99%

Uric acid and the cardio‐renal effects of SGLT2 inhibitors

Bailey

2019

Diabetes Obesity Metabolism

145

118

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Sodium/glucose co-transporter-2 (SGLT2) inhibitors, which lower blood glucose by increasing renal glucose elimination, have been shown to reduce the risk of adverse cardiovascular (CV) and renal events in type 2 diabetes. This has been ascribed, in part, to haemodynamic changes, body weight reduction and several possible effects on myocardial, endothelial and tubulo-glomerular functions, as well as to reduced glucotoxicity. This review evaluates evidence that an effect of SGLT2 inhibitors to lower uric acid may also contribute to reduced cardiorenal risk.Chronically elevated circulating uric acid concentrations are associated with increased risk of hypertension, CV disease and chronic kidney disease (CKD). The extent to which uric acid contributes to these conditions, either as a cause or an aggravating factor, remains unclear, but interventions that reduce urate production or increase urate excretion in hyperuricaemic patients have consistently improved cardio-renal prognoses. Uric acid concentrations are often elevated in type 2 diabetes, contributing to the "metabolic syndrome" of CV risk. Treating type 2 diabetes with an SGLT2 inhibitor increases uric acid excretion, reduces circulating uric acid and improves parameters of CV and renal function. This raises the possibility that the lowering of uric acid by SGLT2 inhibition may assist in reducing adverse CV events and slowing progression of CKD in type 2 diabetes. SGLT2 inhibition might also be useful in the treatment of gout and gouty arthritis, especially when co-existent with diabetes. K E Y W O R D Scardiac, gout, obesity, renal, sodium/glucose co-transporter-2 (SGLT2) inhibitor, type 2 diabetes, uric acid | CARDIO-RENAL EFFECTS OF SGLTINHIBITORSSeveral recent large prospective randomized studies in type 2 diabetes have observed reduced CV risk and improved renal function during treatment with an SGLT2 inhibitor. 3 In the EMPA-REG OUTCOME trial, treatment with empagliflozin was associated with a reduced composite 3-point MACE of CV death, nonfatal myocardial infarction (MI) and stroke by 14%; CV mortality was reduced by 38%, overall mortality by 32% and hospitalization for heart failure by 35%. 4 Empagliflozin also reduced by 39% the deterioration in nephropathy, measured as a composite of progression to macroalbuminuria, doubling of

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The Role of Uric Acid in Kidney Fibrosis: Experimental Evidences for the Causal Relationship

Cited by 62 publications

References 83 publications

Serum Uric Acid and Progression of Kidney Disease: A Longitudinal Analysis and Mini-Review

Serum Uric Acid and Progression of Kidney Disease: A Longitudinal Analysis and Mini-Review

Serum uric acid and the risk of cardiovascular and renal disease

Uric acid and the cardio‐renal effects of SGLT2 inhibitors

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