Paradigm Shift in the Role of Uric Acid in Acute Kidney Injury

Paradigm Shift in the Role of Uric Acid in Acute Kidney Injury Michiko Shimada, MD, PhD,* Bhagwan Dass, MD,† and A. Ahsan Ejaz, MD† Summary: It has been known for decades that uric acid causes acute kidney injury by intratubular crystal precipitation and obstructing the renal tubules. Uric acid crystals stimulate inflammation and elicit immune responses in many disease conditions, including gouty arthritis. More recently, soluble uric acid has been reported to stimulate proliferation of vascular smooth muscle cells, inhibit endothelial function, cause renal vasoconstriction, impair renal blood flow autoregulation, and induce inflammatory response via crystal-independent mechanisms. This article examines the changing role for uric acid in acute kidney injury. Semin Nephrol 31:453-458 © 2011 Elsevier Inc. All rights reserved. Keywords: Uric acid, acute kidney injury

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ric acid has been linked to acute kidney injury (AKI) in various disease states, with the mechanism attributed to intratubular precipitation of uric acid crystals.1 High serum uric acid levels (range, 13-21 mg/dL) and associated intratubular precipitation of uric acid crystals often were present in these cases, commonly referred to as acute urate nephropathy. In an elegant animal experiment, Spencer et al2 showed by micropuncture and clearance studies that oxonic acid/uric acid-induced hyperuricemia in rats were associated with intratubular crystal deposition and a reduction in glomerular filtration rate (GFR), renal blood flow, and filtration fraction. Continuous infusion of uric acid to maintain high serum levels (mean, 19.4 ⫾ 2.2 mg/100 mL) in rats resulted in an acute reduction in renal plasma flow of 83%, GFR of 86%, nephron filtration rate of 66%, and a two-fold increase in tubular and microvascular pressures.3 Thus, the clinicopathologic link between hyperuricemia, tubular deposition of uric acid crystals, and AKI was established. Recently, there has been a paradigm shift regarding the role of uric acid in AKI. Sánchez-Lozada et al4 showed that the earlier-described renal hemodynamic effects also could be induced in rats by mild hyperuricemia without precipitating intratubular crystal deposition. Mild hyperuricemia (uric acid level, 5.4 ⫾ 0.2 mg/dL) induced by oxonic acid in normal and remnant kidney rats was shown to result in afferent arteriole thickening, renal cortical vasoconstriction, decreased single nephron GFR of 35%, and glomerular hypertension, suggesting a crystal-independent mechanism. *Division of Cardiology, Respiratory Medicine and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan. †Division of Nephrology, Hypertension and Transplantation, University of Florida, Gainesville, FL. The authors do not have any conflicts of interest to declare. Address reprint requests to A. Ahsan Ejaz, MD, Division of Nephrology, Hypertension and Transplantation, University of Florida, PO Box 100224, Gainesville, FL 32610-0224. E-mail: ejazaa@ medicine.ufl.edu 0270-9295/ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2011.08.010

Seminars in Nephrology, Vol 31, No 5, September 2011, pp 453-458

The earlier-described observations and the general agreement that renal vasoconstriction5-8 has a central role in the ensuing hypoxia reperfusion injury that sets in motion inflammatory and immunologic pathways that culminate in AKI warrants further investigation regarding the role of uric acid in AKI via crystal-independent pathways. In this article we discuss the available evidence for the role of soluble uric acid (SUA), to this regard.

EPIDEMIOLOGY The association of uric acid with AKI originally was shown in tumor lysis syndrome, in which serum uric acid can increase dramatically after chemotherapy and the massive lysis of proliferating cancers. However, there is also evidence that increases in uric acid may have a role in AKI after cardiovascular surgery or with other procedures. For example, a possible role of increased uric acid has been reported in the pediatric cardiovascular surgery literature. Serum UA levels often are increased in children undergoing cardiovascular surgery.9-11 In one series, anuric AKI was observed in 3 infants who had postoperative SUA levels greater than 20 mg/dL.12 Another study reported that acute increase of SUA was associated with decreased creatinine clearances and that children who died in that study had high postoperative SUA levels of 15 to 17 mg/dL.13 These cases could have been caused by intratubular uric acid crystal deposition, as renal biopsies were not obtained. However, more recent studies have supported the hypothesis that serum uric acid levels in ranges not expected to induce intrarenal crystal deposition also may increase the risk for postoperative AKI. For example, preoperative SUA was shown to be an independent risk factor for AKI in adults undergoing cardiac surgery.14 In this clinical trial, SUA greater than 6 mg/dL was associated with a four-fold increased risk for AKI (odds ratio, 3.98; 95% confidence interval, 1.10-14.33; P ⫽ .035). Other investigators have reported that SUA greater than 6 mg/dL was associated with poor long-term outcome,15 and that it is a predictor of patients at high risk for AKI during natural disasters.16 In addition, prechemotherapy serum uric acid levels greater than 7 mg/dL were associated with a 30-fold increased risk 453

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of adverse renal events in patients at risk for tumor lysis syndrome,17 and decreasing SUA was reported in anecdotal cases to improve established AKI.18,19

PATHOGENESIS Uric Acid Induces Renal Vasoconstriction and Impairs Autoregulation Loss of renal blood flow autoregulation related to renal vasoconstriction is thought to be the initiating event in most forms of AKI.20,21 The evidence that uric acid induces renal vasoconstriction has been present for decades, but hitherto attributed to the downstream effects of intratubular crystal precipitation.2,3,22 However, it has been known that mild asymptomatic hyperuricemia is associated with decreased renal blood flow and increased renal vascular and total peripheral resistances in patients with essential hypertension.23 Dr. Johnson’s group have reported in experimental models that mild hyperuricemia causes renal vasoconstriction, with a 40% to 60% reduction in renal blood flow and a 40% to 50% reduction in single-nephron GFR.4,24 These effects could be reversed by L-arginine, a substrate for endothelial nitric oxide synthase,25 indicating that one of the mechanisms of uric acid–induced renal vasoconstriction was via inhibition of renal neuronal nitric oxide synthase. Hyperuricemia activates primary human vascular endothelial cells, decreases nitric oxide production,26 and inhibits endothelial cell proliferation and migration.27 Direct incubation of aortic rings with uric acid has been shown to impair nitric oxide– dependent endothelial function.28 Soluble uric acid also induces oxidative stress, senescence, and apoptosis in endothelial cells.29 Hyperuricemia also stimulates vascular smooth muscle cell proliferation and migration,27 causes thickening of the preglomerular arterioles, and impairs renal blood flow autoregulation.30 These structural and functional damages are in accordance with a key feature of AKI, wherein oxidative stress from ischemia/reperfusion injury leads to endothelial cell damage, expression, and production of inflammatory mediators and alteration in the vascular response to vasoactive substances.31 Proinflammatory Effects of Uric Acid The loss of balance between vacoconstrictors (angiotensin, endothelin, thromboxane A2, adenosine, sympathetic nerve activity) and vasodilators (nitric oxide, prostaglandin E2) is implicated in the regulation of vascular tone in AKI. A central tenet in support of the renin-angiotensin system in AKI is that sustained and severe vasoconstriction is the strongest event that interrupts renal function. Angiotensin II (Ang II) suppresses nitric oxide synthesis, increases oxidant stress, activates nuclear factor-␬B (NF␬B), stimulates the release of proinflammatory cytokines, and regulates vascular tone.32,33 In this regard, hyperuricemia has been shown to up-regulate the expression of angiotensinogen, angiotensin-converting enzyme, Ang II

M. Shimada, B. Dass, and A.A. Ejaz

receptors, and increase angiotensin II levels.29 Ang II also activates nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase), a common source of superoxide, which consecutively regulates numerous Ang II–mediated effects.34 Sautin et al35 showed that uric acid stimulates NADPH oxidase activity and oxidant production, and resulted in activation of mitogen-activated protein kinases p38 and extracellular-signal-regulated kinases 1/2, and an increase in lipid peroxidation and protein nitrosylation. This array of molecular events in response to uric acid suggests an involvement of the renin-angiotensin system, and clinical data support this contention. In a clinical study of 249 subjects, serum uric acid independently predicted blunted renal vascular responsiveness to Ang II, consistent with results from experimental hyperuricemia showing an activated intrarenal renin-angiotensin system.36 Uric acid also stimulates the expression of proinflammatory molecules monocyte chemoattractant protein-1 (MCP-1),37 C-reactive protein,30 and generation of oxidants and peroxynitrite-associated radicals (ONOO-).38,39 OONO- can stimulate apoptosis through caspase activation or lead to necrosis by peroxidation and nitration. It is reported that ONOO- generated in the tubular epithelium during ischemia/reperfusion injury has the potential to impair the adhesion properties of tubular cells, which then may contribute to the tubular obstruction in AKI.40 Macrophages have long been regarded as classic mediators of innate immunity. This heterogeneous population of cells can induce sterile inflammation after reperfusion directly through the production of proinflammatory cytokines and other soluble inflammatory mediators or indirectly through activation of effector T lymphocytes and natural killer T cells.41 An important feature of renal ischemia/reperfusion injury (IRI) in AKI is the infiltration of polymorphonuclear leukocytes, monocytes, and lymphocytes into the renal tissue.42,43 These cell lineages, stimulated by proinflammatory mediators and microRNAs, are involved in the initial inflammatory response to injury, propagation, and recovery during a postinjury timeline.44,45 The infiltration of monocytes/macrophages is induced by the potent chemoattractant protein MCP-1, the enhanced expression of which is mediated by oxidative stress and NF-␬B activation.33 Uric acid stimulates MCP-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase2,37 and induces the infiltration of inflammatory cells into the renal parenchyma with resultant tissue injury.25,46 There is increasing interest in the role of innate and adaptive immune responses in the pathogenesis of AKI. Uric acid has been found to have a key role in both innate and adaptive immune responses. Peritubular T cells have been observed in AKI and recent data suggest that T cells are important mediators of ischemia/reperfusion injury in AKI.47,48 Increased expression of inter-cellular adhesion molecule-1 and accumulation of monocyte and T cells in the inner stripe of the outer medulla have been shown in the

Uric acid and AKI

early phase of IRI.49 A polarized T-helper cell 1 (Th1) activation response exacerbates renal IRI by increased production of MCP-1.50 Uric acid directly activates primary human T cells in the absence of antigen presentation.51 Microcrystalline uric acid released from dying cells has been reported to be an endogenous danger signal that alerts the immune system to the dying cells through the stimulation of CD8⫹ T cells.52 Uric acid depletion selectively inhibited the inflammatory response to dying cells.53 Furthermore, uric acid crystals can activate inflammasomes, an intracellular multiprotein complex that senses conserved molecular patterns on pathogens.54 Uric acid also has an inflammatory effect on tubular cells as shown by in vitro evidence that uric acid directly induced intercellular adhesion molecule-1 expression in the human proximal tubular cell.55 In AKI, locally released cytokines/chemokines promote intense inflammation in AKI via activated Toll-like receptors, complement cascade, and NF-␬B.56 Uric acid crystals stimulate Toll-like receptors and trigger signaling cascades involving myeloid differentiation factor 88 – dependent and –independent pathways.57

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cantly greater tubular injury scores for both the S3 proximal tubular cells and for collecting duct cells, and caused more interstitial inflammation and peritubular capillaritis. Hyperuricemic rats with cisplatin injury displayed significantly more macrophages in the cortex and inner stripe. This was associated with a three-fold increase in MCP-1 at the levels of messenger RNA and protein, which was measured by quantitative polymerase chain reaction and by enzyme-linked immunosorbent assay, respectively. Decreasing uric acid with recombinant uricase resulted in a significant improvement in renal function, decrease in tubular injury scores, and reduction in the monocyte macrophage infiltration and MCP-1 levels. Recombinant uricase directly decreased uric acid in this study and did not influence the effects of coproduced oxidants generated during the xanthine oxidase reaction on AKI, indicating a more direct role for uric acid per se in accelerating the renal injury. These data provide experimental evidence that uric acid, at concentrations that do not cause intrarenal crystal formation, may exacerbate renal injury in a model of AKI via a proinflammatory pathway involving chemokine expression with leukocyte infiltration.

Uric Acid–Induced Mitochondrial Dysfunction Proximal Tubule as the Site for Uric Acid–Induced AKI

As mentioned previously, uric acid activates Ang II and stimulates NADPH oxidase activity and production of oxidants.35 Ang II is reported to induce mitochondrial dysfunction by activating the endothelial cell NADPH oxidase and formation of peroxynitrite, linking mitochondrial oxidative damage and endothelial dysfunction.58 Mitochondrial dysfunction is a key contributor to renal tubular cell death during AKI and is associated with increased permeability of the mitochondrial outer membrane, release of apoptogenic factors, mitochondrial fragmentation, and consequent apoptosis.59-61 Gentamicin causes AKI by depleting mitochondrial respiratory components (cytochrome c, nicotinamide adenine dinucleotide hydride) by opening mitochondrial transition pores, mediated in part by an increase in reactive oxygen species.62 Recently, hyperuricemia has been reported to worsen gentamicin-induced nephrotoxicity in rats.63 Although the mechanism remains unclear, it is purported that uric acid potentiates the inhibitory action of gentamicin on proximal tubular cell Na⫹/K⫹ adenosine triphosphatase, inhibits tubule cell proliferation, and down-regulates the protective activity of matrix metalloproteinase-9. Whether uric acid directly causes mitochondrial dysfunction is not known.

The anatomic site of renal tissue injury also may support the role of uric acid in AKI via a crystal-independent pathway. Notably, tissue injury in IRI models usually starts as focal S3 proximal tubular damage and extends to the medullary ray and the proximal convoluted tubules in the labyrinth. Distal tubular injury may develop with prolonged and severe injury.64 In the classic reports of urate nephropathy in animal models65 and in human beings,1,22 intrarenal precipitation of uric acid crystals were found to occur in the distal tubules and the collecting ducts. Most cases of urate nephropathy are postulated to be crystal-mediated despite the paucity of evidence for crystal precipitation.1 As mentioned earlier, Roncal et al46 showed in an animal model of AKI that mild hyperuricemia caused S3 proximal tubular injury without intratubular crystal precipitation, consistent with those observed in ischemia/reperfusion injury. Hyperuricemia inhibits proximal tubular cell proliferation in culture by stimulation of mitogen-activated protein kinases and NF␬B.66 Furthermore, hyperuricemia has been shown to stimulate proinflammatory mediators in proximal tubular cells via a ketohexokinase-dependent pathway with stimulation of MCP-1 and oxidative stress.67

Experimental Model of Uric Acid–Induced AKI

Prospective, Randomized, Pilot Clinical Trial

The hypothesis that hyperuricemia, at concentrations that do not promote intrarenal crystal deposition, might exacerbate renal injury and dysfunction was tested in a Sprague-Dawley rat model of cisplatin-induced AKI.46 Hyperuricemia worsened cisplatin-induced S3 proximal tubular injury, brush-border loss, and caused tubular swelling and nuclear condensation, resulting in signifi-

The collective epidemiologic, physiological, experimental, and anecdotal data discussed earlier (Fig. 1) offered enough biological plausibility to test the hypothesis that uric acid may have a role in AKI. In a prospective, double-blind, placebo-controlled, randomized pilot trial of a convenience of 26 (not powered to show differences) adult patients undergoing cardiovascular surgery (tho-

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Figure 1. Proposed mechanisms of uric acid–induced AKI. ICAM-1, intercellular adhesion molecule-1; KHK, keto-hexokinase; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; NO, nitric oxide; PTC, proximal tubule cell; RAS, reninangiotensin system; VEC, vascular endothelial cell; VSMC, vascular smooth muscle cell; TLR, Toll-like receptor.

racic aortic aneurysm, cardiac valve, or coronary artery bypass graft surgery) with an estimated GFR of 30 to 60 mL/min/1.73 m2, and who had a SUA of 6.5 mg/dL or greater were randomized to receive rasburicase or placebo preoperatively to decrease uric acid levels. Urine neutrophil gelatinase-associated lipocalin concentrations and urine interleukin-18 concentrations (uIL-18) of AKI were used as outcome measures.68 The biomarkers urine neutrophil gelatinase-associated lipocalin and uIL-18 have been shown to be reliable and predictive markers of AKI in cardiovascular surgery patients.69 In this study, preoperative decreasing of SUA by rasburicase was associated with a trend toward decreased AKI (7.7% in the treatment group versus 30.8% in the placebo group; P ⫽ .322), and this relationship persisted in patients with more severe cardiac and renal dysfunction. Rasburicase decreased the incidence of AKI by 65% to 70% in the overall study cohort, and this effect reached statistical significance in patients with a GFR of 45 mL/min/1.73 m2 or less (rasburicase 0% versus placebo 75%; P ⫽ .033). Patients with more severe chronic kidney disease appeared to benefit more from intervention to decrease preoperative SUA. Similar results also were observed with uIL-18 measurements. The data suggest that decreasing uric acid might provide renal protection, however, further investigations are required.68

CONCLUSIONS Several physiological properties of hyperuricemia appear to be in accordance with key features of the syndrome of AKI, and experimental and clinical data discussed earlier are supportive of its role in AKI. In contrast, hereditary hypouricemia also has been reported to cause AKI after anaerobic exercise.70 The mechanisms of AKI are different in hypouricemia-induced AKI. These patients have an isolated inborn error of membrane transport of urate in

the renal proximal tubule, often with more generalized proximal tubular disorders.71 It has been reported that homozygous loss-of-function mutations of GLUT9 (SLC2A9) cause a total defect of uric acid absorption, leading to severe renal hypouricemia with marked uricosuria complicated by nephrolithiasis and exercise-induced AKI.72 It is possible that the AKI relates to effects of exerciseinduced volume depletion associated with uricosuria and microcrystal formation. Clearly, more investigations are required to understand the role of SUA in AKI, and larger clinical trials need to be performed to confirm the results obtained to date.

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