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Hyperuricemia and chronic kidney disease: to treat or not to treat

Abstract

Hyperuricemia is common in chronic kidney disease (CKD) and may be present in 50% of patients presenting for dialysis. Hyperuricemia can be secondary to impaired glomerular filtration rate (GFR) that occurs in CKD. However, hyperuricemia can also precede the development of kidney disease and predict incident CKD. Experimental studies of hyperuricemic models have found that both soluble and crystalline uric acid can cause significant kidney damage, characterized by ischemia, tubulointerstitial fibrosis, and inflammation. However, most Mendelian randomization studies failed to demonstrate a causal relationship between uric acid and CKD, and clinical trials have had variable results. Here we suggest potential explanations for the negative clinical and genetic findings, including the role of crystalline uric acid, intracellular uric acid, and xanthine oxidase activity in uric acid-mediated kidney injury. We propose future clinical trials as well as an algorithm for treatment of hyperuricemia in patients with CKD.

Keywords:
Hyperuricemia; Uric Acid; Acute Kidney Injury; Renal Insufficiency, Chronic; Allopurinol; Cardiovascular Disease

Resumo

A hiperuricemia é comum na doença renal crônica (DRC) e pode estar presente em até 50% dos pacientes que se apresentam para diálise. A hiperuricemia pode ser secundária ao comprometimento da taxa de filtração glomerular (TFG) que ocorre na DRC. No entanto, ela também pode preceder o desenvolvimento da doença renal e mesmo prever uma DRC incidente. Estudos experimentais de modelos hiperuricêmicos descobriram que tanto o ácido úrico solúvel quanto o cristalino podem causar danos renais significativos, caracterizados por isquemia, fibrose tubulointersticial e inflamação. Entretanto, a maioria dos estudos de randomização Mendeliana falhou em demonstrar uma relação causal entre o ácido úrico e a DRC, e os ensaios clínicos têm apresentado resultados variáveis. Aqui sugerimos explicações potenciais para os achados clínicos e genéticos negativos, incluindo o papel do ácido úrico cristalino, do ácido úrico intracelular e da atividade da xantina oxidase na lesão renal mediada por ácido úrico. Propomos ensaios clínicos futuros, bem como um algoritmo para o tratamento de hiperuricemia em pacientes com DRC.

Descritores:
Hiperuricemia; Ácido Úrico; Lesão Renal Aguda; Insuficiência Renal Crônica; Alopurinol; Doenças Cardiovasculares

Introduction

The prevalence of chronic kidney disease (CKD) and hyperuricemia is increasing worldwide11 Bardin T, Richette P. Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options. BMC Med. 2017;15(1):123.. CKD is commonly associated with gout, and the association dates back to the mid-nineteenth century22 Davis Junior NS. The cardio-vascular and renal relations and manifestations of gout. JAMA. 1897 Aug;29(6):261-2.,33 Johnson G. On the diseases of the kidney. London: John W Parker and Son; 1852.. Numerous epidemiological studies have consistently shown that hyperuricemia independently predicts new onset CKD44 Krishnan E, Akhras KS, Sharma H, Marynchenko M, Wu E, Tawk RH, et al. Serum urate and incidence of kidney disease among veterans with gout. J Rheumatol. 2013 May;40(7):1166-72.

5 Fuldeore MJ, Riedel AA, Zarotsky V, Pandya BJ, Dabbous O, Krishnan E. Chronic kidney disease in gout in a managed care setting. BMC Nephrol. 2011 Aug;12:36.
-66 Johnson RJ, Nakagawa T, Jalal D, Sánchez-Lozada LG, Kang DH, Ritz E. Uric acid and chronic kidney disease: which is chasing which?. Nephrol Dial Transplant. 2013 Sep;28(9):2221-8.. In addition, hyperuricemia frequently associates with other risk factors for CKD, such as hypertension and metabolic syndrome11 Bardin T, Richette P. Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options. BMC Med. 2017;15(1):123.. However, most Mendelian randomization studies have failed to find a causal relationship77 Jordan DM, Choi HK, Verbanck M, Topless R, Won HH, Nadkarni G, et al. No causal effects of serum urate levels on the risk of chronic kidney disease: a Mendelian randomization study. PLoS Med. 2019 Jan;16(1):e1002725.. Clinical trials have also provided inconsistent data; while earlier trials have generally shown benefit, two recent clinical trials found no effects of lowering serum uric acid in participants with type 1 diabetes with CKD or in patients with non-diabetic CKD (Table 1). Furthermore, it remains debated whether asymptomatic hyperuricemia in the absence of gout confers similar risk for CKD as those with gout44 Krishnan E, Akhras KS, Sharma H, Marynchenko M, Wu E, Tawk RH, et al. Serum urate and incidence of kidney disease among veterans with gout. J Rheumatol. 2013 May;40(7):1166-72.. Here we discuss the controversy of the role of hyperuricemia in CKD, and critically appraise the therapeutic role of lowering serum uric acid in patients with CKD.

Table 1
Clinical studies on uric acid lowering drugs in patients with CKD

Pathogenesis of hyperuricemia in ckd

Although uric acid concentrations are tightly regulated in most species, humans lost this regulatory capacity due to a mutational loss in uricase that degrades uric acid to 5-hydroxyisourate and subsequently allantoin88 Álvarez-Lario B, Macarrón-Vicente J. Uric acid and evolution. Rheumatology (Oxford). 2010 Nov;49(11):2010-5.. A consequence is that serum uric acid can be increased by dietary intake of purine rich foods, fructose, and alcohol. In turn, regulation of uric acid concentrations is primarily via excretion by the kidney (two-thirds of total elimination) and gut (one-third)99 Stewart DJ, Langlois V, Noone D. Hyperuricemia and hypertension: links and risks. Integr Blood Press Control. 2019 Dec;12:43-62.. In addition, a small amount of uric acid is metabolized by oxidants to allantoin, triuret or 6-aminouracil1010 Sanchez-Lozada LG, Rodriguez-Iturbe B, Kelley EE, Nakagawa T, Madero M, Feig DI, et al. Uric acid and hypertension: an update with recommendations. Am J Hypertens. 2020 Jul;33(7):583-94.. In the kidney, uric acid is freely filtered, with a net 90% reabsorbed in the proximal tubule by different transporters (e.g. urate transporter 1 (URAT1), and organic anion transporter 4 (OAT4)), and with approximately 10% excreted1111 Xu X, Li C, Zhou P, Jiang T. Uric acid transporters hiding in the intestine. Pharm Biol. 2016 Dec;54(12):3151-5.. As kidney function declines, uric acid is retained1212 Guan H, Zheng Y, Zhou X, Xu Y, Fu C, Xiao J, et al. Efficacy of different urinary uric acid indicators in patients with chronic kidney disease. BMC Nephrol. 2020 Jul;21:290.. However, it has been demonstrated that renal impairment is accompanied by a significant compensatory increase in the fractional excretion of uric acid (FeUA) and in the excretion of uric acid per volume of glomerular filtration1212 Guan H, Zheng Y, Zhou X, Xu Y, Fu C, Xiao J, et al. Efficacy of different urinary uric acid indicators in patients with chronic kidney disease. BMC Nephrol. 2020 Jul;21:290.. Furthermore, extra-renal uric acid excretion also increases as a compensatory response to reduced kidney excretion of uric acid1313 Fujita K, Yamada H, Iijima M, Ichida K. Electrochemical analysis of uric acid excretion to the intestinal lumen: effect of serum uric acid-lowering drugs and 5/6 nephrectomy on intestinal uric acid levels. PLoS One. 2019 Dec;14(12):e0226918.. Thus, while impaired kidney function will increase serum uric acid levels, its contribution is less than the effects of impaired kidney function on, for example, blood urea nitrogen and creatinine.

While hyperuricemia can result from impaired kidney function, numerous studies have reported that hyperuricemia commonly precedes the development of CKD1414 Zhou F, Yu G, Wang G, Liu Y, Zhang L, Wang W, et al. Association of serum uric acid levels with the incident of kidney disease and rapid eGFR decline in Chinese individuals with eGFR > 60 mL/min/1.73 m2 and negative proteinuria. Clin Exp Nephrol. 2019 Jul;23(7):871-9.

15 Weiner DE, Tighiouart H, Elsayed EF, Griffith JL, Salem DN, Levey AS. Uric acid and incident kidney disease in the community. J Am Soc Nephrol. 2008 Jun;19(6):1204-11.
-1616 Tsai CW, Lin SY, Kuo CC, Huang CC. Serum uric acid and progression of kidney disease: a longitudinal analysis and mini-review. PLoS One. 2017;12(1):e0170393.. This may occur in part because conditions such as obesity, metabolic syndrome, and hypertension are risk factors for CKD and are also commonly associated with hyperuricemia. Proposed mechanisms for the hyperuricemia in these conditions include insulin-dependent reduction in FeUA, hypercholesterolemia-mediated increase in xanthine oxidase (XO) activity, and hypertension-induced afferent arteriolar vasoconstriction with renal retention of uric acid1717 Galvan AQ, Natali A, Baldi S, Frascerra S, Sanna G, Ciociaro D, et al. Effect of insulin on uric acid excretion in humans. Am J Physiol. 1995 Jan;268(1 Pt 1):E1-5.

18 Gwinner W, Scheuer H, Haller H, Brandes RP, Groene HJ. Pivotal role of xanthine oxidase in the initiation of tubulointerstitial renal injury in rats with hyperlipidemia. Kidney Int. 2006 Feb;69(3):481-7.
-1919 Messerli FH, Frohlich ED, Dreslinski GR, Suarez DH, Aristimuno GG. Serum uric acid in essential hypertension: an indicator of renal vascular involvement. Ann Intern Med. 1980 Dec;93(6):817-21..

A genetic predisposition to hyperuricemia and kidney injury has also been shown. In fact, genetic polymorphisms in the regulation of serum uric acid levels have been associated with estimated glomerular filtration rate (eGFR)2020 Macias-Kauffer LR, Villamil-Ramirez H, Leon-Mimila P, Jacobo-Albavera L, Posadas-Romero C, Posadas-Sanchez R, et al. Genetic contributors to serum uric acid levels in Mexicans and their effect on premature coronary artery disease. Int J Cardiol. 2019 Mar;279:168-73.. Additionally, some medications commonly administered to patients with CKD, such as diuretics and immunosuppressants, may also raise serum uric acid concentrations2121 Salem CB, Slim R, Fathallah N, Hmouda H. Drug-induced hyperuricaemia and gout. Rheumatology (Oxford). 2017 May;56(5):679-88..

Epidemiology of the association

Hyperuricemia is a strong independent risk factor for incident CKD(14-16, 22-28). The relationship of serum uric acid with incident CKD is not linear, but risk shows a rapid increase as serum uric acid concentrations reach 7 mg/dL or more2929 Obermayr RP, Temml C, Gutjahr G, Knechtelsdorfer M, Oberbauer R, Klauser-Braun R. Elevated uric acid increases the risk for kidney disease. J Am Soc Nephrol. 2008 Dec;19(12):2407-13.,3030 Iseki K, Oshiro S, Tozawa M, Iseki C, Ikemiya Y, Takishita S. Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects. Hypertens Res. 2001 Nov;24(6):691-7.. In contrast, once patients develop CKD, serum uric acid is more variable, with some studies suggesting it is an independent predictor for worsening of CKD1616 Tsai CW, Lin SY, Kuo CC, Huang CC. Serum uric acid and progression of kidney disease: a longitudinal analysis and mini-review. PLoS One. 2017;12(1):e0170393.,3131 Chonchol M, Shlipak MG, Katz R, Sarnak MJ, Newman AB, Siscovick DS, et al. Relationship of uric acid with progression of kidney disease. Am J Kidney Dis. 2007 Aug;50(2):239-47.,3232 Oh TR, Choi HS, Kim CS, Bae EH, Ma SK, Sung SA, et al. Hyperuricemia has increased the risk of progression of chronic kidney disease: propensity score matching analysis from the KNOW-CKD study. Sci Rep. 2019 Apr;9(1):6681. whereas others studies suggest it is not66 Johnson RJ, Nakagawa T, Jalal D, Sánchez-Lozada LG, Kang DH, Ritz E. Uric acid and chronic kidney disease: which is chasing which?. Nephrol Dial Transplant. 2013 Sep;28(9):2221-8.,3333 Madero M, Sarnak MJ, Wang X, Greene T, Beck GJ, Kusek JW, et al. Uric acid and long-term outcomes in CKD. Am J Kidney Dis. 2009 May;53(5):796-803.. There are also some studies from Japan that suggest a low uric acid may magnify risk for CKD, but this may be due the relatively higher frequency of mutations in the transporter URAT-1 that is associated with severe uricosuria and recurrent acute kidney injury (AKI)3434 Kanda E, Muneyuki T, Kanno Y, Suwa K, Nakajima K. Uric acid level has a U-shaped association with loss of kidney function in healthy people: a prospective cohort study. PLoS One. 2015 Feb;10(2):e0118031.,3535 Mori K, Furuhashi M, Tanaka M, Numata K, Hisasue T, Hanawa N, et al. U-shaped relationship between serum uric acid level and decline in renal function during a 10-year period in female subjects: BOREAS-CKD2. Hypertens Res. 2020 Aug;44(1):107-16..

Some genetic studies also suggest that hyperuricemia may confer risk for CKD, especially in Mexican American, Native American, and Italian populations2020 Macias-Kauffer LR, Villamil-Ramirez H, Leon-Mimila P, Jacobo-Albavera L, Posadas-Romero C, Posadas-Sanchez R, et al. Genetic contributors to serum uric acid levels in Mexicans and their effect on premature coronary artery disease. Int J Cardiol. 2019 Mar;279:168-73.,3636 Testa A, Mallamaci F, Spoto B, Pisano A, Sanguedolce MC, Tripepi G, et al. Association of a polymorphism in a gene encoding a urate transporter with CKD progression. Clin J Am Soc Nephrol. 2014 Jun;9(6):1059-65.,3737 Voruganti VS, Franceschini N, Haack K, Laston S, MacCluer JW, Umans JG, et al. Replication of the effect of SLC2A9 genetic variation on serum uric acid levels in American Indians. Eur J Hum Genet. 2014 Jul;22(7):938-43.. However, a recent large Mendelian randomization study did not find any association between serum uric acid, eGFR, and CKD77 Jordan DM, Choi HK, Verbanck M, Topless R, Won HH, Nadkarni G, et al. No causal effects of serum urate levels on the risk of chronic kidney disease: a Mendelian randomization study. PLoS Med. 2019 Jan;16(1):e1002725..

These controversial results could be a consequence of selection biases due to the heterogeneity of the hyperuricemic population. For example, it may make a difference whether the hyperuricemia is primary (e.g., dietary or from increased synthesis) or secondary (e.g., due to passive retention from attenuated renal excretion due to an impaired eGFR). Another variable could be the level of hyperuricemia, for, as mentioned, the relationship between serum uric acid levels and the development of CKD is not linear but increases exponentially for values of serum uric acid > 7 mg/dL and especially > 9 mg/dL1616 Tsai CW, Lin SY, Kuo CC, Huang CC. Serum uric acid and progression of kidney disease: a longitudinal analysis and mini-review. PLoS One. 2017;12(1):e0170393.,2929 Obermayr RP, Temml C, Gutjahr G, Knechtelsdorfer M, Oberbauer R, Klauser-Braun R. Elevated uric acid increases the risk for kidney disease. J Am Soc Nephrol. 2008 Dec;19(12):2407-13.,3232 Oh TR, Choi HS, Kim CS, Bae EH, Ma SK, Sung SA, et al. Hyperuricemia has increased the risk of progression of chronic kidney disease: propensity score matching analysis from the KNOW-CKD study. Sci Rep. 2019 Apr;9(1):6681.,3838 Rincon-Choles H, Jolly SE, Arrigain S, Konig V, Schold JD, Nakhoul G, et al. Impact of uric acid levels on kidney disease progression. Am J Nephrol. 2017;46(4):315-22.. It is also plausible that it may relate to whether there is crystal deposition in the kidney, which might be expected to be higher in patients with gout, although people with asymptomatic hyperuricemia may also have silent crystal deposition in joints and other organs3939 Klauser AS, Halpern EJ, Strobl S, Gruber J, Feuchtner G, Bellmann-Weiler R, et al. Dual-energy computed tomography detection of cardiovascular monosodium urate deposits in patients with gout. JAMA Cardiol. 2019 Oct;4(10):1019-28.,4040 Khanna P, Johnson RJ, Marder B, LaMoreaux B, Kumar A. Systemic urate deposition: an unrecognized complication of gout?. J Clin Med. 2020 Oct;9(10):3204.. Indeed, gout has been associated with a higher risk of advanced CKD compared to asymptomatic hyperuricemia4141 Stack AG, Johnson ME, Blak B, Klein A, Carpenter L, Morlock R, et al. Gout and the risk of advanced chronic kidney disease in the UK health system: a national cohort study. BMJ Open. 2019;9(8):e031550.,4242 Badve SV, Brown F, Hawley CM, Johnson DW, Kanellis J, Rangan GK, et al. Challenges of conducting a trial of uric-acid-lowering therapy in CKD. Nat Rev Nephrol. 2011 May;7(5):295-300.. It is thus evident how prior studies are not easily generalizable, as distinct subgroups of people with hyperuricemia may show a different risk of CKD.

There is also some evidence that the biologic effects of uric acid to cause kidney disease may be mediated more by the intracellular effects of uric acid as opposed to serum uric acid4343 Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, et al. A role for uric acid in the progression of renal disease. J Am Soc Nephrol. 2002 Dec;13(12):2888-97.,4444 Kang DH, Park SK, Lee IK, Johnson RJ. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol. 2005 Dec;16(12):3553-62.. Intracellular levels might be higher in the setting where synthesis is stimulated, such as may be observed with high xanthine oxidoreductase (XO) activity. Plasma XO activity is associated with CKD progression and cardiovascular outcomes, independently of serum uric acid4545 Gondouin B, Jourde-Chiche N, Sallee M, Dou L, Cerini C, Loundou A, et al. Plasma xanthine oxidase activity is predictive of cardiovascular disease in patients with chronic kidney disease, independently of uric acid levels. Nephron. 2015;131(3):167-74.,4646 Kim YJ, Oh SH, Ahn JS, Yook JM, Kim CD, Park SH, et al. The crucial role of xanthine oxidase in CKD progression associated with hypercholesterolemia. Int J Mol Sci. 2020 Oct;21(20):7444.. This could potentially explain why serum uric acid may not predict CKD by Mendelian randomization studies, as the polymorphisms in urate transporters that predict hyperuricemia may have different effects on intracellular uric acid concentrations4747 DeBosch BJ, Kluth O, Fujiwara H, Schurmann A, Moley K. Early-onset metabolic syndrome in mice lacking the intestinal uric acid transporter SLC2A9. Nat Commun. 2014 Aug;5:4642..

Does uric acid cause kidney injury?

Hyperuricemia is thought to cause kidney injury by both crystal-dependent and crystal-independent mechanisms4848 Piani F, Johnson RJ. Does gouty nephropathy exist, and is it more common than we think? Kidney Int. 2021 Jan;99(1):31-33. doi: 10.1016/j.kint.2020.10.015. PMID: 33390238.
https://doi.org/10.1016/j.kint.2020.10.0...
(Figure 1).

Figure 1
Mechanisms of uric acid-induced kidney injury.

The crystal-dependent pathway involves the deposition of monosodium urate crystals in the tubules or interstitium in the kidney in the outer medulla that leads to chronic inflammation and tubular damage4848 Piani F, Johnson RJ. Does gouty nephropathy exist, and is it more common than we think? Kidney Int. 2021 Jan;99(1):31-33. doi: 10.1016/j.kint.2020.10.015. PMID: 33390238.
https://doi.org/10.1016/j.kint.2020.10.0...
. Recently it has been suggested that this can be diagnosed by renal ultrasound showing a “hyperechoic” outer medulla, and that it may be present in one-third of patients with gout where it correlates with kidney function4949 Bardin T, Nguyen QD, Tran KM, Le NH, Do MD, Richette P, et al. A cross sectional study of 502 patients found a diffuse hyperechoic kidney medulla pattern in patients with severe gout. Kidney Int. 2021 Jan;99(1):218-26.. Interestingly, the presence of this microcrystalline nephropathy was not associated with urinary evidence for urate crystalluria, underlying the independence of the two pathophysiologic mechanisms4949 Bardin T, Nguyen QD, Tran KM, Le NH, Do MD, Richette P, et al. A cross sectional study of 502 patients found a diffuse hyperechoic kidney medulla pattern in patients with severe gout. Kidney Int. 2021 Jan;99(1):218-26.. Of note, urate crystals have also been discovered to deposit in both the aorta and coronary arteries, where they may have a role in plaque formation and vascular calcification4040 Khanna P, Johnson RJ, Marder B, LaMoreaux B, Kumar A. Systemic urate deposition: an unrecognized complication of gout?. J Clin Med. 2020 Oct;9(10):3204.. As such, the crystal-dependent pathway may also be a mechanism by which uric acid may be involved in the pathogenesis of atherosclerosis and heart disease.

Soluble, intracellular uric acid may also cause CKD via a crystal-independent process. This may occur by either uptake of uric acid from the circulation or by endogenous generation such as from dietary fructose5050 Sánchez-Lozada LG. The pathophysiology of uric acid on renal diseases. Contrib Nephrol. 2018;192:17-24.. The mechanism involves elevations in both systemic and intraglomerular pressure coupled with afferent arteriolar vasoconstriction with impaired renal blood flow that is mediated by activation of the renin angiotensin aldosterone (RAAS) system, a reduction in endothelial nitric oxide bioavailability and the induction of oxidative stress5151 Sanchez-Lozada LG, Soto V, Tapia E, Avila-Casado C, Sautin YY, Nakagawa T, et al. Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia. Am J Physiol Renal Physiol. 2008 Oct;295(4):F1134-41.,5252 Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001 Nov;38(5):1101-6.. There is also vascular smooth muscle cell proliferation that leads to an arteriolopathy that impairs autoregulation, and also effects on tubules that include epithelial-mesenchymal changes and inflammatory changes5353 Ryu ES, Kim MJ, Shin HS, Jang YH, Choi HS, Jo I, et al. Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease. Am J Physiol Renal Physiol. 2013 Mar;304(5):F471-80.

54 Verzola D, Ratto E, Villaggio B, Parodi EL, Pontremoli R, Garibotto G, et al. Uric acid promotes apoptosis in human proximal tubule cells by oxidative stress and the activation of NADPH oxidase NOX 4. PLoS One. 2014 Dec;9(12):e115210.
-5555 Zhou Y, Fang L, Jiang L, Wen P, Cao H, He W, et al. Uric acid induces renal inflammation via activating tubular NF-kappaB signaling pathway. PLoS One. 2012;7(6):e39738.. Indeed, ischemia is one of the main pathology findings in both human and animal kidney of subjects affected by hyperuricemia and gout5656 Sanchez-Lozada LG, Tapia E, Santamaría J, Avila-Casado C, Soto V, Nepomuceno T, et al. Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats. Kidney Int. 2005 Jan;67(1):237-47.. Of note, most of the animal studies on hyperuricemia have used the oxonic acid-induced hyperuricemic rat model5757 Stavric B, Nera EA, Johnson WJ, Salem FA. Uric acid kidney stones induced in rats by oxonic acid, a uricase inhibitor. Invest Urol. 1973 Jul;11(1):3-8..

Clinical trials of uric acid in chronic kidney disease

Experimental trials of uric acid lowering drugs in CKD have been mixed (Table 1). One analysis suggested that a primary reason for the mixed results was that some trials were too short or underpowered to show meaningful progression in the control groups, thus making it difficult to show a benefit in the treatment group. In essence, if the control group does not demonstrate worsening of the underlying disease, it is challenging for any treatment to demonstrate protection. Indeed, studies showing meaningful progression (defined as ≥4 mL/min/1.73m22 Davis Junior NS. The cardio-vascular and renal relations and manifestations of gout. JAMA. 1897 Aug;29(6):261-2. decrease in the control group over the time course of the study) were associated with a benefit of urate-lowering therapy. This analysis argued for urate-lowering therapy in participants with hyperuricemia and CKD5858 Sato Y, Feig DI, Stack AG, Kang DH, Lanaspa MA, Ejaz AA, et al. The case for uric acid-lowering treatment in patients with hyperuricaemia and CKD. Nat Rev Nephrol. 2019 Dec;15(12):767-75..

More recently, two large clinical trials, the Preventing Early Renal Loss in Diabetes (PERL) and the Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase (CKD-FIX) studies, were published in which significant progression did occur in the control groups but for which no benefit in treatment of uric acid levels were noted5959 Doria A, Galecki AT, Spino C, Pop-Busui R, Cherney DZ, Lingvay I, et al. Serum urate lowering with allopurinol and kidney function in type 1 diabetes. N Engl J Med. 2020 Jun;382(26):2493-503.,6060 Badve SV, Pascoe EM, Tiku A, Boudville N, Brown FG, Cass A, et al. Effects of allopurinol on the progression of chronic kidney disease. N Engl J Med. 2020 Jun;382(26):2504-13.. The PERL was well designed but the participants who had type 1 diabetes did not have gout, and the majority had normal serum uric acid concentrations. The CKD-FIX also did not enroll participants with gout and included subjects irrespective of their serum uric acid concentration. Both groups also had dropout rates greater than 15 percent which were included in the analysis as they were intention-to-treat studies. Hence, neither study targeted the population at risk, that being participants with hyperuricemia with or without gout, and thus conclusions on treating hyperuricemia in CKD are still unclear.

Treatment recommendations

Before any recommendations are provided, it is important to discuss the potential toxicities of the various treatments. Allopurinol is a xanthine oxidase inhibitor that is usually well tolerated, but it can be associated with a severe hypersensitivity syndrome mimicking a Stevens Johnson syndrome in individuals carrying the HLA B58 allele6161 Jung JW, Song WJ, Kim YS, Joo KW, Lee KW, Kim SH, et al. HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency. Nephrol Dial Transplant. 2011 Nov;26(11):3567-72.. This is especially common in the Asian population. The other common xanthine oxidase inhibitor, febuxostat, does not appear to have this side effect but was associated with increased all-cause and cardiovascular mortality compared to allopurinol in the CARES trial (62), although another recently published trial did not observe any difference between allopurinol and febuxostat on cardiovascular outcomes6363 Mackenzie IS, Ford I, Nuki G, Hallas J, Hawkey CJ, Webster J, et al. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020 Nov;396(10264):1745-57.. In the CARES trial, most of the cardiovascular events occurred after the febuxostat was stopped6464 Johnson TA, Kamatani N, Kuwabara M. Xanthine oxidase inhibitor withdrawal syndrome? comment on the article by Choi et al. Arthritis Rheumatol. 2019 Nov;71(11):1966-7.. Stopping xanthine oxidase inhibitors has been associated with worsening of kidney function in patients with CKD, but only in those who are not on RAAS blockers6565 Talaat KM, El-Sheikh AR. The effect of mild hyperuricemia on urinary transforming growth factor beta and the progression of chronic kidney disease. Am J Nephrol. 2007;27(5):435-40.. Since treatment of xanthine oxidase inhibitors is known to block the RAAS6666 Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA. 2008 Aug;300(8):924-32., it is possible that stopping xanthine oxidase inhibitors could cause a rebound activation of the RAAS.

Other uric acid lowering agents include uricosurics, but these are not recommended in patients with CKD as acute rises in urine uric acid may cause transient worsening of kidney function. However, this may be mitigated by combining a uricosuric with a xanthine oxidase inhibitor. Finally, uric acid can also be lowered by recombinant uricases such as pegloticase and rasburicase. However, some individuals may develop antibodies to these agents that can limit their eventual effectiveness.

Clearly, more clinical trials are needed. However, based on the fact that marked hyperuricemia appears to carry significant risk for kidney disease progression that could involve both crystal-dependent and -independent mechanisms, we suggest that treatment should be considered for individuals with serum uric acid concentrations of 8 mg/dL or higher and evidence of progression of their kidney disease, as well as patients with a history of gout irrespective of their underlying serum uric acid concentration. In Table 1 we summarized the main clinical studies on uric acid lowering drugs in patients with CKD. We would recommend assessing if patients are on a RAAS inhibitor before initiating allopurinol (beginning with low doses of 50 mg daily with slow titling to a maximum of 300 mg/daily). All patients are told to stop allopurinol if they develop a rash, and those of Asian ancestry should consider HLA typing prior to drug initiation. Alternatives to allopurinol could include febuxostat or combination uricosuric-xanthine oxidase combinations. Pegloticase can also be used for those with severe and refractory gout.

In summary, hyperuricemia is a risk factor for CKD, and there is strong evidence that it can cause kidney disease by either crystal-dependent or -independent mechanisms. Nevertheless, trials examining the effects of uric acid lowering interventions in CKD have been inconsistent, although this be ascribed to the trials not targeting the participants most likely to benefit, which are those with hyperuricemia and/or a history of gout. Until further trials are done, we still would recommend urate-lowering drugs for this target population provided they show evidence of progression of their kidney disease. Careful attention to the potential toxicities of urate-lowering drugs is needed.

References

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Publication Dates

  • Publication in this collection
    05 Mar 2021
  • Date of issue
    Oct-Dec 2021

History

  • Received
    16 Dec 2020
  • Accepted
    28 Dec 2020
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