Cardiac and renal protective effects of urate-lowering therapy

Cardiac and renal protective effects of urate-lowering therapy Abstract Patients with gout often have co-morbidities such as cardiovascular disease, renal failure and metabolic syndrome components. Some studies, but not all, have suggested that hyperuricaemia and gout are associated with increased risk of myocardial infarction, renal failure and death primarily because of increased risk of cardiovascular events. Therefore, knowledge of the effects of urate-lowering therapy (ULT) on co-morbidities, in particular cardiovascular events and chronic kidney disease, is crucial. Randomized controlled trials (RCTs) have suggested that allopurinol, a xanthine oxidase inhibitor, could improve exercise capacity in patients with chronic stable angina and could decrease blood pressure in adolescents. In contrast, a well-designed RCT found no effect of allopurinol in patients with heart failure. The impact of ULT in patients with chronic kidney disease is unclear. Some RCTs found that allopurinol could slow the decline in kidney function, whereas a recent controlled trial found no benefit of febuxostat. Large randomized placebo-controlled trials are warranted to confirm or not the benefit of ULT on co-morbidities. urate-lowering therapy, gout, co-morbidities, allopurinol, febuxostat Rheumatology key messages The causality between hyperuricaemia, gout and co-morbidities is controversial. Some randomized controlled trials have suggested that urate-lowering therapies might have cardiac and renal benefit. Large randomized placebo-controlled trials are warranted to confirm or not the benefit of urate-lowering therapy for cardiorenal co-morbidities. Introduction Gout is strongly associated with several co-morbidities, particularly traditional vascular risk factors and chronic kidney disease (CKD) [1–3]. Data from epidemiological studies have suggested that gout and hyperuricaemia are independent risk factors for cardiovascular (CV) diseases and renal dysfunction [4]. In addition, animal studies have uncovered a mechanistic approach to the vascular toxicity of uric acid [5]. However, the causality between hyperuricaemia and these outcomes remains uncertain because confounders, reverse causality or common aetiological factors might explain these epidemiological results. These uncertainties have not been solved by recent studies involving Mendelian randomization. Overall, data from these recent studies are negative: most, but not all [6–8], found no association between hyperuricaemia, CV diseases [9, 10] and CKD [11] or metabolic syndrome components [12, 13]. Causality can also be addressed by investigating the effect of urate-lowering therapy (ULT) on co-morbidities, therefore knowledge of the effects of ULT on CV and renal outcomes is of major interest. ULT and CV outcomes The mechanisms that may link hyperuricaemia and gout with CV events are unclear but may include oxidative stress generated by xanthine oxidase (XO), the enzyme that catalyzes the formation of urate [4, 14]. Other explanations are a direct contribution to endothelial dysfunction [5] and low-grade inflammation associated with increased urate levels and tophi [15]. Recently a cross-sectional study showed that coronary heart disease could be more severe in hyperuricaemic patients with asymptomatic monosodium urate crystal deposition than normouricaemic or hyperuricaemic patients without crystal deposits, which suggests a vascular deleterious effect of monosodium urate crystals [16]. Small randomized trials found that XO inhibitors (XOIs) improved endothelial dysfunction and decreased oxidative stress in patients with stable coronary artery disease [17]. Two small randomized placebo-controlled trials found that high-dose allopurinol (600 mg/day) led to regression of left ventricular mass in 66 patients with ischaemic heart disease [18] and enhanced exercise capacity in 65 with chronic stable angina [19]. Except for one study [20], pharmaco-epidemiological studies also suggested a benefit of XOIs in patients with coronary artery disease, with reduced risk of myocardial infarction in those receiving allopurinol [21–23]. Data for patients with heart failure (HF) are more controversial. Large epidemiological studies found that allopurinol decreased morbidity and mortality rates in patients with congestive heart failure and a history of gout [17]. Similarly, in an observational study, allopurinol was associated with an ∼30% reduced risk of readmission for HF or death in patients with a history of gout [24]. However, the sole well-designed randomized controlled trial (RCT) of patients with HF (n = 253) had negative results. Patients (n = 253) with symptomatic HF and hyperuricaemia [serum uric acid (sUA) level ⩾9.5 mg/dl] were randomized to receive allopurinol (600 mg/day) or a placebo in a double-blind, multicentre trial. The primary composite endpoint at 24 weeks was based on survival, worsening HF and patient global assessment. At 24 weeks, clinical status did not differ between the allopurinol- and placebo-treated patients [25]. ULT seems to have a beneficial effect on blood pressure (BP), but only in obese adolescents [26]. In one trial of adolescents (n = 30) with hyperuricaemia and newly diagnosed hypertension, treatment with allopurinol (400 mg/day) normalized BP in 66% of patients [27]. In another placebo-controlled study of 60 adolescents with obesity and pre-hypertension, allopurinol ⩽400 mg/day) or probenecid (⩽1 g/day) markedly reduced ambulatory systolic and diastolic BP, which suggests that the BP lowering resulted from sUA reduction [28]. However, these results cannot be extended to adults: a recent RCT reported that ULT did not change adult BP [24]. In this trial, 149 overweight and obese adults with an sUA level ⩾5.0 mg/dl were randomized to receive probenecid (500 mg once daily), allopurinol (300 mg once daily) or a placebo for 8 weeks. At the end of the study period, BP did not differ among the treatments [29]. Impact of ULT in CKD patients The prevalence of CKD stage ⩾3 in gout was estimated at 24% in a recent meta-analysis of six studies [30]. Reduced kidney function decreases urate excretion in urine and increases the risk of gout. In a large German CKD patient cohort, gout prevalence ranged from 16.0 to 35.6% for CKD patients with an estimated glomerular filtration rate (eGFR) >60 and <30 ml/min/1.73 m2, respectively [31]. More recently, the 3-year incidence of gout in older patients with CKD was reported. The incidence in men was 0.8 and 4.6% for those with eGFR ⩾90 and ⩽30 ml/min/1.73 m2, respectively [32]. Conversely, the risk of end-stage renal failure was found to be increased in patients with gout [33] and the risk of CKD increased in patients with asymptomatic hyperuricaemia [34, 35]. These findings can be explained by the formation of uric acid crystals in renal tubules, interstitial nephritis complicating kidney stones, crystalline deposits in the renal medulla [36], use of NSAIDs, a frequent association with hypertension or the possible renal toxicity of soluble uric acid [37]. A meta-analysis of 19 RCTs based on 992 participants found a small but statistically significant improvement in eGFR [mean difference 3.2 ml/min/1.73 m2 (95% CI 0.16, 6.2); P = 0.039] and serum creatinine level [mean difference 0.63 mg/dl (95% CI 0.43, 0.82); P < 0.001] in patients with stages 3–5 CKD who were taking allopurinol for 4–24 months [38]. A placebo-controlled monocentric RCT of 93 hyperuricaemic CKD patients suggested that febuxostat (40 mg daily) could have similar beneficial effects at 6 months [39]. The mean eGFR in the febuxostat group showed a non-significant increase from 31.5 ml/min/1.73 m2 (s.d. 13.6) to 34.7 (s.d. 18.1) at 6 months. In contrast, the mean eGFR in the placebo group decreased from 32.6 ml/min/m2 (s.d. 11.6) to 28.2 (11.5) (P = 0.003). The difference between groups was 6.5 ml/min/1.73 m2 (95% CI 0.08, 12.81) at 6 months (P = 0.05). However, this renoprotective effect of febuxostat was not observed in a recent randomized placebo-controlled trial of 96 gout patients with moderate to severe renal impairment [40]. ULT and mortality Several studies found gout associated with increased mortality, mainly due to CV events [4, 41, 42]. For instance, in the National Health and Nutrition Examination Survey trial (n = 15 773 participants), mortality was increased 50% for gouty patients, with a 1 mg/dl increase in sUA level associated with a 28% increase in mortality [43]. A recent meta-analysis of RCTs assessed the effect of ULT on mortality. Pooled results from eight studies (n = 2221 participants) did not demonstrate a statistically significant difference in all-cause mortality when comparing any ULT (allopurinol or febuxostat) with placebo. However, the limited number of events precludes drawing any firm conclusions [44]. Conclusions The causality between hyperuricaemia, gout and co-morbidities is still controversial. Some RCTs, but not all, have suggested that urate-lowering drug levels might have cardiac and renal benefits. However, the level of evidence provided by these RCTs, with often small sample sizes, is not great. Given the lack of clear evidence for the cardiorenal benefit of ULT, as well as the uncertainty about progression from asymptomatic hyperuricaemia to symptomatic disease in all patients, neither the EULAR [45], British Society for Rheumatology [46] or ACR [47] currently recommend ULT for the management of asymptomatic hyperuricaemia. Large randomized placebo-controlled trials are warranted to confirm or not the benefit of ULT for cardiorenal co-morbidities. Supplement: This supplement was funded by Grunenthal. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: P.R. received fees for consultancy work or talks from AstraZeneca, Grunenthal, Ipsen, Menarini and Savient. T.B. received research grants from AstraZeneca, Ipsen and Menarini and fees for consultancy work or talks from Astella, AstraZeneca, Biomex, Grunenthal, Ipsen, Menarini, Novartis, Savient and Sobi. The other author has declared no conflicts of interest. References 1 Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet  2016; 388: 2039– 52. http://dx.doi.org/10.1016/S0140-6736(16)00346-9 Google Scholar CrossRef Search ADS PubMed  2 Kuo CF, Grainge MJ, Mallen C, Zhang W, Doherty M. Comorbidities in patients with gout prior to and following diagnosis: case-control study. Ann Rheum Dis  2016; 75: 210– 7. http://dx.doi.org/10.1136/annrheumdis-2014-206410 Google Scholar CrossRef Search ADS PubMed  3 Richette P, Clerson P, Perissin L, Flipo RM, Bardin T. Revisiting comorbidities in gout: a cluster analysis. Ann Rheum Dis  2015; 74: 142– 7. Google Scholar CrossRef Search ADS PubMed  4 Richette P, Perez-Ruiz F, Doherty M et al.   Improving cardiovascular and renal outcomes in gout: what should we target? Nat Rev Rheumatol  2014; 10: 654– 61. Google Scholar CrossRef Search ADS PubMed  5 Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med  2008; 359: 1811– 21. http://dx.doi.org/10.1056/NEJMra0800885 Google Scholar CrossRef Search ADS PubMed  6 Yan D, Wang J, Jiang F et al.   A causal relationship between uric acid and diabetic macrovascular disease in Chinese type 2 diabetes patients: a Mendelian randomization analysis. Int J Cardiol  2016; 214: 194– 9. http://dx.doi.org/10.1016/j.ijcard.2016.03.206 Google Scholar CrossRef Search ADS PubMed  7 Kleber ME, Delgado G, Grammer TB et al.   Uric acid and cardiovascular events: a Mendelian randomization study. J Am Soc Nephrol  2015; 26: 2831– 8. http://dx.doi.org/10.1681/ASN.2014070660 Google Scholar CrossRef Search ADS PubMed  8 Hughes K, Flynn T, de Zoysa J, Dalbeth N, Merriman TR. Mendelian randomization analysis associates increased serum urate, due to genetic variation in uric acid transporters, with improved renal function. Kidney Int  2014; 85: 344– 51. http://dx.doi.org/10.1038/ki.2013.353 Google Scholar CrossRef Search ADS PubMed  9 Palmer TM, Nordestgaard BG, Benn M et al.   Association of plasma uric acid with ischaemic heart disease and blood pressure: Mendelian randomisation analysis of two large cohorts. BMJ  2013; 347: f4262 Google Scholar CrossRef Search ADS PubMed  10 Keenan T, Zhao W, Rasheed A et al.   Causal assessment of serum urate levels in cardiometabolic diseases through a Mendelian randomization study. J Am Coll Cardiol  2016; 67: 407– 16. http://dx.doi.org/10.1016/j.jacc.2015.10.086 Google Scholar CrossRef Search ADS PubMed  11 Yang Q, Kottgen A, Dehghan A et al.   Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ Cardiovasc Genet  2010; 3: 523– 30. http://dx.doi.org/10.1161/CIRCGENETICS.109.934455 Google Scholar CrossRef Search ADS PubMed  12 White J, Sofat R, Hemani G et al.   Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis. Lancet Diabetes Endocrinol  2016; 4: 327– 36. http://dx.doi.org/10.1016/S2213-8587(15)00386-1 Google Scholar CrossRef Search ADS PubMed  13 Sluijs I, Holmes MV, van der Schouw YT et al.   A Mendelian randomization study of circulating uric acid and type 2 diabetes. Diabetes  2015; 64: 3028– 36. http://dx.doi.org/10.2337/db14-0742 Google Scholar CrossRef Search ADS PubMed  14 Okafor ON, Farrington K, Gorog DA. Allopurinol as a therapeutic option in cardiovascular disease. Pharmacol Ther  2017; 172: 139– 50. http://dx.doi.org/10.1016/j.pharmthera.2016.12.004 Google Scholar CrossRef Search ADS PubMed  15 Perez-Ruiz F, Martinez-Indart L, Carmona L et al.   Tophaceous gout and high level of hyperuricaemia are both associated with increased risk of mortality in patients with gout. Ann Rheum Dis  2014; 73: 177– 82. Google Scholar CrossRef Search ADS PubMed  16 Andres M, Quintanilla MA, Sivera F et al.   Silent monosodium urate crystal deposits are associated with severe coronary calcification in asymptomatic hyperuricemia: an exploratory study. Arthritis Rheumatol  2016; 68: 1531– 9. http://dx.doi.org/10.1002/art.39581 Google Scholar CrossRef Search ADS PubMed  17 Higgins P, Dawson J, Lees KR et al.   Xanthine oxidase inhibition for the treatment of cardiovascular disease: a systematic review and meta-analysis. Cardiovasc Ther  2012; 30: 217– 26. http://dx.doi.org/10.1111/j.1755-5922.2011.00277.x Google Scholar CrossRef Search ADS PubMed  18 Rekhraj S, Gandy SJ, Szwejkowski BR et al.   High-dose allopurinol reduces left ventricular mass in patients with ischemic heart disease. J Am Coll Cardiol  2013; 61: 926– 32. http://dx.doi.org/10.1016/j.jacc.2012.09.066 Google Scholar CrossRef Search ADS PubMed  19 Noman A, Ang DS, Ogston S, Lang CC, Struthers AD. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet  2010; 375: 2161– 7. http://dx.doi.org/10.1016/S0140-6736(10)60391-1 Google Scholar CrossRef Search ADS PubMed  20 Kok VC, Horng JT, Chang WS, Hong YF, Chang TH. Allopurinol therapy in gout patients does not associate with beneficial cardiovascular outcomes: a population-based matched-cohort study. PLoS One  2014; 9: e99102 Google Scholar CrossRef Search ADS PubMed  21 de Abajo FJ, Gil MJ, Rodriguez A et al.   Allopurinol use and risk of non-fatal acute myocardial infarction. Heart  2015; 101: 679– 85. http://dx.doi.org/10.1136/heartjnl-2014-306670 Google Scholar CrossRef Search ADS PubMed  22 Grimaldi-Bensouda L, Alperovitch A, Aubrun E et al.   Impact of allopurinol on risk of myocardial infarction. Ann Rheum Dis  2015; 74: 836– 42. Google Scholar CrossRef Search ADS PubMed  23 Larsen KS, Pottegard A, Lindegaard HM, Hallas J. Effect of allopurinol on cardiovascular outcomes in hyperuricemic patients: a cohort study. Am J Med  2016; 129:299–306 e2. 24 Thanassoulis G, Brophy JM, Richard H, Pilote L. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med  2010; 170: 1358– 64. Google Scholar CrossRef Search ADS PubMed  25 Givertz MM, Anstrom KJ, Redfield MM et al.   Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the EXACT-HF study. Circulation  2015; 131: 1763– 71. http://dx.doi.org/10.1161/CIRCULATIONAHA.114.014536 Google Scholar CrossRef Search ADS PubMed  26 Agarwal V, Hans N, Messerli FH. Effect of allopurinol on blood pressure: a systematic review and meta-analysis. J Clin Hypertens  2013; 15: 435– 42. http://dx.doi.org/10.1111/j.1751-7176.2012.00701.x Google Scholar CrossRef Search ADS   27 Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA  2008; 300: 924– 32. http://dx.doi.org/10.1001/jama.300.8.924 Google Scholar CrossRef Search ADS PubMed  28 Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension  2012; 60: 1148– 56. http://dx.doi.org/10.1161/HYPERTENSIONAHA.112.196980 Google Scholar CrossRef Search ADS PubMed  29 McMullan CJ, Borgi L, Fisher N, Curhan G, Forman J. Effect of uric acid lowering on renin-angiotensin-system activation and ambulatory BP: a randomized controlled trial. Clin J Am Soc Nephrol  2017; 12: 807– 16. Google Scholar CrossRef Search ADS PubMed  30 Roughley MJ, Belcher J, Mallen CD, Roddy E. Gout and risk of chronic kidney disease and nephrolithiasis: meta-analysis of observational studies. Arthritis Res Ther  2015; 17: 90 http://dx.doi.org/10.1186/s13075-015-0610-9 Google Scholar CrossRef Search ADS PubMed  31 Jing J, Kielstein JT, Schultheiss UT et al.   Prevalence and correlates of gout in a large cohort of patients with chronic kidney disease: the German Chronic Kidney Disease (GCKD) study. Nephrol Dial Transplant  2015; 30: 613– 21. http://dx.doi.org/10.1093/ndt/gfu352 Google Scholar CrossRef Search ADS PubMed  32 Tan VS, Garg AX, McArthur E et al.   The 3-year incidence of gout in elderly patients with CKD. Clin J Am Soc Nephrol  2017; 12: 577– 84. http://dx.doi.org/10.2215/CJN.06790616 Google Scholar CrossRef Search ADS PubMed  33 Yu KH, Kuo CF, Luo SF et al.   Risk of end-stage renal disease associated with gout: a nationwide population study. Arthritis Res Ther  2012; 14: R83 Google Scholar CrossRef Search ADS PubMed  34 Kuwabara M, Niwa K, Hisatome I et al.   Asymptomatic hyperuricemia without comorbidities predicts cardiometabolic diseases: five-year Japanese cohort study. Hypertension  2017; 69: 1036– 44. http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.08998 Google Scholar CrossRef Search ADS PubMed  35 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: e0170393 Google Scholar CrossRef Search ADS PubMed  36 Ayoub I, Almaani S, Brodsky S et al.   Revisiting medullary tophi: a link between uric acid and progressive chronic kidney disease? Clin Nephrol  2016; 85: 109– 13. Google Scholar CrossRef Search ADS PubMed  37 Li L, Yang C, Zhao Y et al.   Is hyperuricemia an independent risk factor for new-onset chronic kidney disease?: a systematic review and meta-analysis based on observational cohort studies. BMC Nephrol  2014; 15: 122 http://dx.doi.org/10.1186/1471-2369-15-122 Google Scholar CrossRef Search ADS PubMed  38 Kanji T, Gandhi M, Clase CM, Yang R. Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis. BMC Nephrol  2015; 16: 58. http://dx.doi.org/10.1186/s12882-015-0047-z Google Scholar CrossRef Search ADS PubMed  39 Sircar D, Chatterjee S, Waikhom R et al.   Efficacy of febuxostat for slowing the GFR decline in patients with CKD and asymptomatic hyperuricemia: a 6-month, double-blind, randomized, placebo-controlled trial. Am J Kidney Dis  2015; 66: 945– 50. http://dx.doi.org/10.1053/j.ajkd.2015.05.017 Google Scholar CrossRef Search ADS PubMed  40 Saag KG, Whelton A, Becker MA et al.   Impact of febuxostat on renal function in gout patients with moderate-to-severe renal impairment. Arthritis Rheumatol  2016; 68: 2035– 43. http://dx.doi.org/10.1002/art.39654 Google Scholar CrossRef Search ADS PubMed  41 Fisher MC, Rai SK, Lu N, Zhang Y, Choi HK. The unclosing premature mortality gap in gout: a general population-based study. Ann Rheum Dis  2017; 76: 1289– 94. http://dx.doi.org/10.1136/annrheumdis-2016-210588 Google Scholar CrossRef Search ADS PubMed  42 Kuo CF, Grainge MJ, Zhang W, Doherty M. Global epidemiology of gout: prevalence, incidence and risk factors. Nat Rev Rheumatol  2015; 11: 649– 62. http://dx.doi.org/10.1038/nrrheum.2015.91 Google Scholar CrossRef Search ADS PubMed  43 Stack AG, Hanley A, Casserly LF et al.   Independent and conjoint associations of gout and hyperuricaemia with total and cardiovascular mortality. QJM  2013; 106: 647– 58. http://dx.doi.org/10.1093/qjmed/hct083 Google Scholar CrossRef Search ADS PubMed  44 Zhang T, Pope JE. Cardiovascular effects of urate-lowering therapies in patients with chronic gout: a systematic review and meta-analysis. Rheumatology  2017; 56: 1144– 53. http://dx.doi.org/10.1093/rheumatology/kex065 Google Scholar CrossRef Search ADS PubMed  45 Richette P, Doherty M, Pascual E et al.   2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis  2017; 76: 29– 42. http://dx.doi.org/10.1136/annrheumdis-2016-209707 Google Scholar CrossRef Search ADS PubMed  46 Hui M, Carr A, Cameron S et al.   The British Society for Rheumatology guideline for the management of gout. Rheumatology  2017; 56: e1– 20. Google Scholar CrossRef Search ADS PubMed  47 Khanna D, Fitzgerald JD, Khanna PP et al.   2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res  2012; 64: 1431– 46. Google Scholar CrossRef Search ADS   © The Author 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Cardiac and renal protective effects of urate-lowering therapy

Loading next page...
 
/lp/ou_press/cardiac-and-renal-protective-effects-of-urate-lowering-therapy-njcCzKizo5
Publisher
Oxford University Press
Copyright
© The Author 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
ISSN
1462-0324
eISSN
1462-0332
D.O.I.
10.1093/rheumatology/kex432
Publisher site
See Article on Publisher Site

Abstract

Abstract Patients with gout often have co-morbidities such as cardiovascular disease, renal failure and metabolic syndrome components. Some studies, but not all, have suggested that hyperuricaemia and gout are associated with increased risk of myocardial infarction, renal failure and death primarily because of increased risk of cardiovascular events. Therefore, knowledge of the effects of urate-lowering therapy (ULT) on co-morbidities, in particular cardiovascular events and chronic kidney disease, is crucial. Randomized controlled trials (RCTs) have suggested that allopurinol, a xanthine oxidase inhibitor, could improve exercise capacity in patients with chronic stable angina and could decrease blood pressure in adolescents. In contrast, a well-designed RCT found no effect of allopurinol in patients with heart failure. The impact of ULT in patients with chronic kidney disease is unclear. Some RCTs found that allopurinol could slow the decline in kidney function, whereas a recent controlled trial found no benefit of febuxostat. Large randomized placebo-controlled trials are warranted to confirm or not the benefit of ULT on co-morbidities. urate-lowering therapy, gout, co-morbidities, allopurinol, febuxostat Rheumatology key messages The causality between hyperuricaemia, gout and co-morbidities is controversial. Some randomized controlled trials have suggested that urate-lowering therapies might have cardiac and renal benefit. Large randomized placebo-controlled trials are warranted to confirm or not the benefit of urate-lowering therapy for cardiorenal co-morbidities. Introduction Gout is strongly associated with several co-morbidities, particularly traditional vascular risk factors and chronic kidney disease (CKD) [1–3]. Data from epidemiological studies have suggested that gout and hyperuricaemia are independent risk factors for cardiovascular (CV) diseases and renal dysfunction [4]. In addition, animal studies have uncovered a mechanistic approach to the vascular toxicity of uric acid [5]. However, the causality between hyperuricaemia and these outcomes remains uncertain because confounders, reverse causality or common aetiological factors might explain these epidemiological results. These uncertainties have not been solved by recent studies involving Mendelian randomization. Overall, data from these recent studies are negative: most, but not all [6–8], found no association between hyperuricaemia, CV diseases [9, 10] and CKD [11] or metabolic syndrome components [12, 13]. Causality can also be addressed by investigating the effect of urate-lowering therapy (ULT) on co-morbidities, therefore knowledge of the effects of ULT on CV and renal outcomes is of major interest. ULT and CV outcomes The mechanisms that may link hyperuricaemia and gout with CV events are unclear but may include oxidative stress generated by xanthine oxidase (XO), the enzyme that catalyzes the formation of urate [4, 14]. Other explanations are a direct contribution to endothelial dysfunction [5] and low-grade inflammation associated with increased urate levels and tophi [15]. Recently a cross-sectional study showed that coronary heart disease could be more severe in hyperuricaemic patients with asymptomatic monosodium urate crystal deposition than normouricaemic or hyperuricaemic patients without crystal deposits, which suggests a vascular deleterious effect of monosodium urate crystals [16]. Small randomized trials found that XO inhibitors (XOIs) improved endothelial dysfunction and decreased oxidative stress in patients with stable coronary artery disease [17]. Two small randomized placebo-controlled trials found that high-dose allopurinol (600 mg/day) led to regression of left ventricular mass in 66 patients with ischaemic heart disease [18] and enhanced exercise capacity in 65 with chronic stable angina [19]. Except for one study [20], pharmaco-epidemiological studies also suggested a benefit of XOIs in patients with coronary artery disease, with reduced risk of myocardial infarction in those receiving allopurinol [21–23]. Data for patients with heart failure (HF) are more controversial. Large epidemiological studies found that allopurinol decreased morbidity and mortality rates in patients with congestive heart failure and a history of gout [17]. Similarly, in an observational study, allopurinol was associated with an ∼30% reduced risk of readmission for HF or death in patients with a history of gout [24]. However, the sole well-designed randomized controlled trial (RCT) of patients with HF (n = 253) had negative results. Patients (n = 253) with symptomatic HF and hyperuricaemia [serum uric acid (sUA) level ⩾9.5 mg/dl] were randomized to receive allopurinol (600 mg/day) or a placebo in a double-blind, multicentre trial. The primary composite endpoint at 24 weeks was based on survival, worsening HF and patient global assessment. At 24 weeks, clinical status did not differ between the allopurinol- and placebo-treated patients [25]. ULT seems to have a beneficial effect on blood pressure (BP), but only in obese adolescents [26]. In one trial of adolescents (n = 30) with hyperuricaemia and newly diagnosed hypertension, treatment with allopurinol (400 mg/day) normalized BP in 66% of patients [27]. In another placebo-controlled study of 60 adolescents with obesity and pre-hypertension, allopurinol ⩽400 mg/day) or probenecid (⩽1 g/day) markedly reduced ambulatory systolic and diastolic BP, which suggests that the BP lowering resulted from sUA reduction [28]. However, these results cannot be extended to adults: a recent RCT reported that ULT did not change adult BP [24]. In this trial, 149 overweight and obese adults with an sUA level ⩾5.0 mg/dl were randomized to receive probenecid (500 mg once daily), allopurinol (300 mg once daily) or a placebo for 8 weeks. At the end of the study period, BP did not differ among the treatments [29]. Impact of ULT in CKD patients The prevalence of CKD stage ⩾3 in gout was estimated at 24% in a recent meta-analysis of six studies [30]. Reduced kidney function decreases urate excretion in urine and increases the risk of gout. In a large German CKD patient cohort, gout prevalence ranged from 16.0 to 35.6% for CKD patients with an estimated glomerular filtration rate (eGFR) >60 and <30 ml/min/1.73 m2, respectively [31]. More recently, the 3-year incidence of gout in older patients with CKD was reported. The incidence in men was 0.8 and 4.6% for those with eGFR ⩾90 and ⩽30 ml/min/1.73 m2, respectively [32]. Conversely, the risk of end-stage renal failure was found to be increased in patients with gout [33] and the risk of CKD increased in patients with asymptomatic hyperuricaemia [34, 35]. These findings can be explained by the formation of uric acid crystals in renal tubules, interstitial nephritis complicating kidney stones, crystalline deposits in the renal medulla [36], use of NSAIDs, a frequent association with hypertension or the possible renal toxicity of soluble uric acid [37]. A meta-analysis of 19 RCTs based on 992 participants found a small but statistically significant improvement in eGFR [mean difference 3.2 ml/min/1.73 m2 (95% CI 0.16, 6.2); P = 0.039] and serum creatinine level [mean difference 0.63 mg/dl (95% CI 0.43, 0.82); P < 0.001] in patients with stages 3–5 CKD who were taking allopurinol for 4–24 months [38]. A placebo-controlled monocentric RCT of 93 hyperuricaemic CKD patients suggested that febuxostat (40 mg daily) could have similar beneficial effects at 6 months [39]. The mean eGFR in the febuxostat group showed a non-significant increase from 31.5 ml/min/1.73 m2 (s.d. 13.6) to 34.7 (s.d. 18.1) at 6 months. In contrast, the mean eGFR in the placebo group decreased from 32.6 ml/min/m2 (s.d. 11.6) to 28.2 (11.5) (P = 0.003). The difference between groups was 6.5 ml/min/1.73 m2 (95% CI 0.08, 12.81) at 6 months (P = 0.05). However, this renoprotective effect of febuxostat was not observed in a recent randomized placebo-controlled trial of 96 gout patients with moderate to severe renal impairment [40]. ULT and mortality Several studies found gout associated with increased mortality, mainly due to CV events [4, 41, 42]. For instance, in the National Health and Nutrition Examination Survey trial (n = 15 773 participants), mortality was increased 50% for gouty patients, with a 1 mg/dl increase in sUA level associated with a 28% increase in mortality [43]. A recent meta-analysis of RCTs assessed the effect of ULT on mortality. Pooled results from eight studies (n = 2221 participants) did not demonstrate a statistically significant difference in all-cause mortality when comparing any ULT (allopurinol or febuxostat) with placebo. However, the limited number of events precludes drawing any firm conclusions [44]. Conclusions The causality between hyperuricaemia, gout and co-morbidities is still controversial. Some RCTs, but not all, have suggested that urate-lowering drug levels might have cardiac and renal benefits. However, the level of evidence provided by these RCTs, with often small sample sizes, is not great. Given the lack of clear evidence for the cardiorenal benefit of ULT, as well as the uncertainty about progression from asymptomatic hyperuricaemia to symptomatic disease in all patients, neither the EULAR [45], British Society for Rheumatology [46] or ACR [47] currently recommend ULT for the management of asymptomatic hyperuricaemia. Large randomized placebo-controlled trials are warranted to confirm or not the benefit of ULT for cardiorenal co-morbidities. Supplement: This supplement was funded by Grunenthal. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: P.R. received fees for consultancy work or talks from AstraZeneca, Grunenthal, Ipsen, Menarini and Savient. T.B. received research grants from AstraZeneca, Ipsen and Menarini and fees for consultancy work or talks from Astella, AstraZeneca, Biomex, Grunenthal, Ipsen, Menarini, Novartis, Savient and Sobi. The other author has declared no conflicts of interest. References 1 Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet  2016; 388: 2039– 52. http://dx.doi.org/10.1016/S0140-6736(16)00346-9 Google Scholar CrossRef Search ADS PubMed  2 Kuo CF, Grainge MJ, Mallen C, Zhang W, Doherty M. Comorbidities in patients with gout prior to and following diagnosis: case-control study. Ann Rheum Dis  2016; 75: 210– 7. http://dx.doi.org/10.1136/annrheumdis-2014-206410 Google Scholar CrossRef Search ADS PubMed  3 Richette P, Clerson P, Perissin L, Flipo RM, Bardin T. Revisiting comorbidities in gout: a cluster analysis. Ann Rheum Dis  2015; 74: 142– 7. Google Scholar CrossRef Search ADS PubMed  4 Richette P, Perez-Ruiz F, Doherty M et al.   Improving cardiovascular and renal outcomes in gout: what should we target? Nat Rev Rheumatol  2014; 10: 654– 61. Google Scholar CrossRef Search ADS PubMed  5 Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med  2008; 359: 1811– 21. http://dx.doi.org/10.1056/NEJMra0800885 Google Scholar CrossRef Search ADS PubMed  6 Yan D, Wang J, Jiang F et al.   A causal relationship between uric acid and diabetic macrovascular disease in Chinese type 2 diabetes patients: a Mendelian randomization analysis. Int J Cardiol  2016; 214: 194– 9. http://dx.doi.org/10.1016/j.ijcard.2016.03.206 Google Scholar CrossRef Search ADS PubMed  7 Kleber ME, Delgado G, Grammer TB et al.   Uric acid and cardiovascular events: a Mendelian randomization study. J Am Soc Nephrol  2015; 26: 2831– 8. http://dx.doi.org/10.1681/ASN.2014070660 Google Scholar CrossRef Search ADS PubMed  8 Hughes K, Flynn T, de Zoysa J, Dalbeth N, Merriman TR. Mendelian randomization analysis associates increased serum urate, due to genetic variation in uric acid transporters, with improved renal function. Kidney Int  2014; 85: 344– 51. http://dx.doi.org/10.1038/ki.2013.353 Google Scholar CrossRef Search ADS PubMed  9 Palmer TM, Nordestgaard BG, Benn M et al.   Association of plasma uric acid with ischaemic heart disease and blood pressure: Mendelian randomisation analysis of two large cohorts. BMJ  2013; 347: f4262 Google Scholar CrossRef Search ADS PubMed  10 Keenan T, Zhao W, Rasheed A et al.   Causal assessment of serum urate levels in cardiometabolic diseases through a Mendelian randomization study. J Am Coll Cardiol  2016; 67: 407– 16. http://dx.doi.org/10.1016/j.jacc.2015.10.086 Google Scholar CrossRef Search ADS PubMed  11 Yang Q, Kottgen A, Dehghan A et al.   Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ Cardiovasc Genet  2010; 3: 523– 30. http://dx.doi.org/10.1161/CIRCGENETICS.109.934455 Google Scholar CrossRef Search ADS PubMed  12 White J, Sofat R, Hemani G et al.   Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis. Lancet Diabetes Endocrinol  2016; 4: 327– 36. http://dx.doi.org/10.1016/S2213-8587(15)00386-1 Google Scholar CrossRef Search ADS PubMed  13 Sluijs I, Holmes MV, van der Schouw YT et al.   A Mendelian randomization study of circulating uric acid and type 2 diabetes. Diabetes  2015; 64: 3028– 36. http://dx.doi.org/10.2337/db14-0742 Google Scholar CrossRef Search ADS PubMed  14 Okafor ON, Farrington K, Gorog DA. Allopurinol as a therapeutic option in cardiovascular disease. Pharmacol Ther  2017; 172: 139– 50. http://dx.doi.org/10.1016/j.pharmthera.2016.12.004 Google Scholar CrossRef Search ADS PubMed  15 Perez-Ruiz F, Martinez-Indart L, Carmona L et al.   Tophaceous gout and high level of hyperuricaemia are both associated with increased risk of mortality in patients with gout. Ann Rheum Dis  2014; 73: 177– 82. Google Scholar CrossRef Search ADS PubMed  16 Andres M, Quintanilla MA, Sivera F et al.   Silent monosodium urate crystal deposits are associated with severe coronary calcification in asymptomatic hyperuricemia: an exploratory study. Arthritis Rheumatol  2016; 68: 1531– 9. http://dx.doi.org/10.1002/art.39581 Google Scholar CrossRef Search ADS PubMed  17 Higgins P, Dawson J, Lees KR et al.   Xanthine oxidase inhibition for the treatment of cardiovascular disease: a systematic review and meta-analysis. Cardiovasc Ther  2012; 30: 217– 26. http://dx.doi.org/10.1111/j.1755-5922.2011.00277.x Google Scholar CrossRef Search ADS PubMed  18 Rekhraj S, Gandy SJ, Szwejkowski BR et al.   High-dose allopurinol reduces left ventricular mass in patients with ischemic heart disease. J Am Coll Cardiol  2013; 61: 926– 32. http://dx.doi.org/10.1016/j.jacc.2012.09.066 Google Scholar CrossRef Search ADS PubMed  19 Noman A, Ang DS, Ogston S, Lang CC, Struthers AD. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet  2010; 375: 2161– 7. http://dx.doi.org/10.1016/S0140-6736(10)60391-1 Google Scholar CrossRef Search ADS PubMed  20 Kok VC, Horng JT, Chang WS, Hong YF, Chang TH. Allopurinol therapy in gout patients does not associate with beneficial cardiovascular outcomes: a population-based matched-cohort study. PLoS One  2014; 9: e99102 Google Scholar CrossRef Search ADS PubMed  21 de Abajo FJ, Gil MJ, Rodriguez A et al.   Allopurinol use and risk of non-fatal acute myocardial infarction. Heart  2015; 101: 679– 85. http://dx.doi.org/10.1136/heartjnl-2014-306670 Google Scholar CrossRef Search ADS PubMed  22 Grimaldi-Bensouda L, Alperovitch A, Aubrun E et al.   Impact of allopurinol on risk of myocardial infarction. Ann Rheum Dis  2015; 74: 836– 42. Google Scholar CrossRef Search ADS PubMed  23 Larsen KS, Pottegard A, Lindegaard HM, Hallas J. Effect of allopurinol on cardiovascular outcomes in hyperuricemic patients: a cohort study. Am J Med  2016; 129:299–306 e2. 24 Thanassoulis G, Brophy JM, Richard H, Pilote L. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med  2010; 170: 1358– 64. Google Scholar CrossRef Search ADS PubMed  25 Givertz MM, Anstrom KJ, Redfield MM et al.   Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the EXACT-HF study. Circulation  2015; 131: 1763– 71. http://dx.doi.org/10.1161/CIRCULATIONAHA.114.014536 Google Scholar CrossRef Search ADS PubMed  26 Agarwal V, Hans N, Messerli FH. Effect of allopurinol on blood pressure: a systematic review and meta-analysis. J Clin Hypertens  2013; 15: 435– 42. http://dx.doi.org/10.1111/j.1751-7176.2012.00701.x Google Scholar CrossRef Search ADS   27 Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA  2008; 300: 924– 32. http://dx.doi.org/10.1001/jama.300.8.924 Google Scholar CrossRef Search ADS PubMed  28 Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension  2012; 60: 1148– 56. http://dx.doi.org/10.1161/HYPERTENSIONAHA.112.196980 Google Scholar CrossRef Search ADS PubMed  29 McMullan CJ, Borgi L, Fisher N, Curhan G, Forman J. Effect of uric acid lowering on renin-angiotensin-system activation and ambulatory BP: a randomized controlled trial. Clin J Am Soc Nephrol  2017; 12: 807– 16. Google Scholar CrossRef Search ADS PubMed  30 Roughley MJ, Belcher J, Mallen CD, Roddy E. Gout and risk of chronic kidney disease and nephrolithiasis: meta-analysis of observational studies. Arthritis Res Ther  2015; 17: 90 http://dx.doi.org/10.1186/s13075-015-0610-9 Google Scholar CrossRef Search ADS PubMed  31 Jing J, Kielstein JT, Schultheiss UT et al.   Prevalence and correlates of gout in a large cohort of patients with chronic kidney disease: the German Chronic Kidney Disease (GCKD) study. Nephrol Dial Transplant  2015; 30: 613– 21. http://dx.doi.org/10.1093/ndt/gfu352 Google Scholar CrossRef Search ADS PubMed  32 Tan VS, Garg AX, McArthur E et al.   The 3-year incidence of gout in elderly patients with CKD. Clin J Am Soc Nephrol  2017; 12: 577– 84. http://dx.doi.org/10.2215/CJN.06790616 Google Scholar CrossRef Search ADS PubMed  33 Yu KH, Kuo CF, Luo SF et al.   Risk of end-stage renal disease associated with gout: a nationwide population study. Arthritis Res Ther  2012; 14: R83 Google Scholar CrossRef Search ADS PubMed  34 Kuwabara M, Niwa K, Hisatome I et al.   Asymptomatic hyperuricemia without comorbidities predicts cardiometabolic diseases: five-year Japanese cohort study. Hypertension  2017; 69: 1036– 44. http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.08998 Google Scholar CrossRef Search ADS PubMed  35 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: e0170393 Google Scholar CrossRef Search ADS PubMed  36 Ayoub I, Almaani S, Brodsky S et al.   Revisiting medullary tophi: a link between uric acid and progressive chronic kidney disease? Clin Nephrol  2016; 85: 109– 13. Google Scholar CrossRef Search ADS PubMed  37 Li L, Yang C, Zhao Y et al.   Is hyperuricemia an independent risk factor for new-onset chronic kidney disease?: a systematic review and meta-analysis based on observational cohort studies. BMC Nephrol  2014; 15: 122 http://dx.doi.org/10.1186/1471-2369-15-122 Google Scholar CrossRef Search ADS PubMed  38 Kanji T, Gandhi M, Clase CM, Yang R. Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis. BMC Nephrol  2015; 16: 58. http://dx.doi.org/10.1186/s12882-015-0047-z Google Scholar CrossRef Search ADS PubMed  39 Sircar D, Chatterjee S, Waikhom R et al.   Efficacy of febuxostat for slowing the GFR decline in patients with CKD and asymptomatic hyperuricemia: a 6-month, double-blind, randomized, placebo-controlled trial. Am J Kidney Dis  2015; 66: 945– 50. http://dx.doi.org/10.1053/j.ajkd.2015.05.017 Google Scholar CrossRef Search ADS PubMed  40 Saag KG, Whelton A, Becker MA et al.   Impact of febuxostat on renal function in gout patients with moderate-to-severe renal impairment. Arthritis Rheumatol  2016; 68: 2035– 43. http://dx.doi.org/10.1002/art.39654 Google Scholar CrossRef Search ADS PubMed  41 Fisher MC, Rai SK, Lu N, Zhang Y, Choi HK. The unclosing premature mortality gap in gout: a general population-based study. Ann Rheum Dis  2017; 76: 1289– 94. http://dx.doi.org/10.1136/annrheumdis-2016-210588 Google Scholar CrossRef Search ADS PubMed  42 Kuo CF, Grainge MJ, Zhang W, Doherty M. Global epidemiology of gout: prevalence, incidence and risk factors. Nat Rev Rheumatol  2015; 11: 649– 62. http://dx.doi.org/10.1038/nrrheum.2015.91 Google Scholar CrossRef Search ADS PubMed  43 Stack AG, Hanley A, Casserly LF et al.   Independent and conjoint associations of gout and hyperuricaemia with total and cardiovascular mortality. QJM  2013; 106: 647– 58. http://dx.doi.org/10.1093/qjmed/hct083 Google Scholar CrossRef Search ADS PubMed  44 Zhang T, Pope JE. Cardiovascular effects of urate-lowering therapies in patients with chronic gout: a systematic review and meta-analysis. Rheumatology  2017; 56: 1144– 53. http://dx.doi.org/10.1093/rheumatology/kex065 Google Scholar CrossRef Search ADS PubMed  45 Richette P, Doherty M, Pascual E et al.   2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis  2017; 76: 29– 42. http://dx.doi.org/10.1136/annrheumdis-2016-209707 Google Scholar CrossRef Search ADS PubMed  46 Hui M, Carr A, Cameron S et al.   The British Society for Rheumatology guideline for the management of gout. Rheumatology  2017; 56: e1– 20. Google Scholar CrossRef Search ADS PubMed  47 Khanna D, Fitzgerald JD, Khanna PP et al.   2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res  2012; 64: 1431– 46. Google Scholar CrossRef Search ADS   © The Author 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Journal

RheumatologyOxford University Press

Published: Jan 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off