Original Article

Uric Acid Control in Advanced Chronic Kidney Disease in a Southeastern US Urban Cohort

Authors: Tibor Fülöp, MD, PhD, Christian A. Koch, MD, PhD, MACE, Lindsey T. Norris, MD, Betzaida Rodríguez, MD, Tibor Szarvas, PhD, Zsolt Lengvárszky, PhD, Éva Csongrádi, MD, PhD, Mehul P. Dixit, MD

Abstract

Objectives: Uric acid (UA) control may be insufficient in chronic kidney disease (CKD) patients in the current era. It is unclear, however, whether this is the result of environmental effects, patient anthropometrics or insufficient dosing of medical therapy (allopurinol).

Methods: We have collected data on multiple clinical and laboratory parameters of 114 CKD clinic patients attending the nephrology clinic of the University of Mississippi Medical Center with an estimated glomerular filtration rate <45 mL · min−1 · 1.73 m2. We assessed the correlates of UA levels and the allopurinol doses along with achieved serum UA and urine pH.

Results: The cohort consisted of middle-aged to elderly patients with a mean (± standard deviation) age of 62.1 (11.6) years; 45.6% were female, 68.4% were African American and 47.4% had a history of gout. The mean UA level was 7.7 (2.49) mg/dL (range 3.1–16), allopurinol dose was 192 (99) mg/day (range 50–450) and estimated glomerular filtration rate was 23.8 (11.3) mL · min−1 · 1.73 m2. While the overall serum bicarbonate level was 25 (3.2) mEq/L, urine pH was <6 in 60.5% of the cohort. Significant univariate correlates of the administered doses of allopurinol were weight (r 0.317, P = 0.001), body mass index (BMI; r 0.313, P = 0.001), and female sex (r −0.198; P = 0.035). Achieved UA levels correlated directly with BMI (r 0.201, r = 0.036) but inversely with the allopurinol dose (r −0.196; P = 0.036). During logistic regression analysis with stepwise selection, only weight (β 0.313, P = 0.001) and sex (β −0.190, P = 0.039) proved to be predictive of the allopurinol dose; as for the achieved UA level, only BMI (β 0.271, P = 0.006) and the allopurinol dose (β −0.258; P = 0.009) had a significant effect.

Conclusions: In patients with advanced CKD, conventional dosing recommendations for allopurinol are unlikely to suffice in reaching target serum UA goals. In our cohort, larger-than-usual allopurinol doses were well tolerated.

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References

1. Dousdampanis P, Trigka K, Musso CG, et al. Hyperuricemia and chronic kidney disease: an enigma yet to be solved. RenFail 2014;36:1351-1359.
 
2. Johnson RJ, Nakagawa T, Jalal D, et al. Uric acid and chronic kidney disease: which is chasing which? Nephrol Dial Transplant 2013;28:2221-2228.
 
3. Hirotsu C, Tufik S, Guindalini C, et al. Association between uric acid levels and obstructive sleep apnea syndrome in a large epidemiological sample. PLoS One 2013;8:e66891.
 
4. Karis E, Crittenden DB, Pillinger MH. Hyperuricemia, gout, and related comorbidities: cause and effect on a two-way street. South Med J 2014;107: 235-241.
 
5. Jalal DI, Chonchol M, Chen W, et al. Uric acid as a target of therapy in CKD. Am J Kidney Dis 2013;61:134-146.
 
6. Mwasongwe S, Fülöp T, Min YI, et al. Relation of Uric Acid Level to Rapid Kidney Function Decline and Development of Kidney Disease among African Americans in the Jackson Heart Study. J Clin Hypertens 2018; 20 :775-783.
 
7. DailyMed. Label: zyloprim-allopurinol tablet. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=13564. Accessed September 4, 2017.
 
8. Flessner MF, Wyatt SB, Akylbekova EL, et al. Prevalence and awareness of CKD among African Americans: the Jackson heart study. Am J Kidney Dis 2009;53:238-247.
 
9. Wang W, Young BA, Fulop T, et al. Effects of serum creatinine calibration on estimated renal function in african americans: the Jackson heart study. Am J Med Sci 2015;349:379-384.
 
10. Zsom L, Zsom M, Fulop T, et al. Correlation of treatment time and ultrafiltration rate with serum albumin and C-reactive protein levels in patients with end-stage kidney disease receiving chronic maintenance hemodialysis: a cross-sectional study. Blood Purif 2010;30:8-15.
 
11. Satchidanand N, Withiam-Leitch M, Dickinson M, et al. Positive predictive value of a single assessment of estimated GFR in the diagnosis of chronic kidney disease. South Med J 2016;109:351-355.
 
12. Weiner DE, Tighiouart H, Elsayed EF, et al. Uric acid and incident kidney disease in the community. J Am Soc Nephrol 2008;19:1204-1211.
 
13. Obermayr RP, Temml C, Gutjahr G, et al. Elevated uric acid increases the risk for kidney disease. J Am Soc Nephrol 2008;19:2407-2413.
 
14. Zoppini G, Targher G, Chonchol M, et al. Serum uric acid levels and incident chronic kidney disease in patients with type 2 diabetes and preserved kidney function. Diabetes Care 2012;35:99-104.
 
15. Juraschek SP, Appel LJ, Miller ER 3rd. Metoprolol increases uric acid and risk of gout in African Americans with chronic kidney disease attributed to hypertension. Am J Hypertens 2017;30:871-875.
 
16. Juraschek SP, Kovell LC, Miller ER 3rd, et al. Gout, urate-lowering therapy, and uric acid levels among adults in the United States. Arthritis Care Res (Hoboken) 2015;67:588-592.
 
17. Desideri G, Castaldo G, Lombardi A, et al. Is it time to revise the normal range of serum uric acid levels. Eur Rev Med Pharmacol Sci 2014;18: 1295-1306.
 
18. 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 (Hoboken) 2012;64:1431-1446.
 
19. Seth R, Kydd AS, Buchbinder R, et al. Allopurinol for chronic gout. Cochrane Database Syst Rev 2014;10:CD006077.
 
20. Rutherford E, Stewart G, Houston JG, et al. An open-label dose-finding study of allopurinol to target defined reduction in urate levels in hemodialysis patients. J Clin Pharmacol 2017;57:1409-1414.
 
21. Siu YP, Leung KT, Tong MK, et al. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis 2006;47:51-59.
 
22. Goicoechea M, de Vinuesa SG, Verdalles U, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol 2010;5:1388-1393.
 
23. Yelken B, Caliskan Y, Gorgulu N, et al. Reduction of uric acid levels with allopurinol treatment improves endothelial function in patients with chronic kidney disease. Clin Nephrol 2012;77:275-282.
 
24. Kanji T, Gandhi M, Clase CM, et al. Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis. BMC Nephrol 2015;16:58.
 
25. Golmohammadi S, Almasi A, Manouchehri M, et al. Allopurinol against progression of chronic kidney disease. Iran J Kidney Dis 2017;11:286-293.
 
26. Pai BH, Swarnalatha G, Ram R, et al. Allopurinol for prevention of progression of kidney disease with hyperuricemia. Indian J Nephrol 2013;23:280-286.
 
27. Krishnamurthy A, Lazaro D, Stefanov DG, et al. The effect of allopurinol on renal function. J Clin Rheumatol 2017;23:1-5.
 
28. Chao J, Terkeltaub R. A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout. Curr Rheumatol Rep 2009;11:135-140.
 
29. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984;76:47-56.
 
30. Sakai Y, Otsuka T, Ohno D, et al. Febuxostat for treating allopurinol-resistant hyperuricemia in patients with chronic kidney disease. Ren Fail 2014;36: 225-231.
 
31. Vazquez-Mellado J, Morales EM, Pacheco-Tena C, et al. Relation between adverse events associated with allopurinol and renal function in patients with gout. Ann Rheum Dis 2001;60:981-983.
 
32. Dalbeth N, Kumar S, Stamp L, et al. Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricemia in patients with gout. J Rheumatol 2006;33:1646-1650.
 
33. Stamp LK, O'Donnell JL, Zhang M, et al. Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. Arthritis Rheum 2011;63:412-421.
 
34. Takahashi S, Nakashima A, Urabe A, et al. Effects of switching from allopurinol to febuxostat in chronic kidney disease patients. Adv Modern Med 2017;:325.
 
35. Singh JA, Cleveland JD. Comparative effectiveness of allopurinol versus febuxostat for preventing incident renal disease in older adults: an analysis of Medicare claims data. Ann Rheum Dis 2017;76:1669-1678.
 
36. Liu CT, Chen CY, Hsu CY, et al. Risk of febuxostat-associated myopathy in patients with CKD. Clin J Am Soc Nephrol 2017;12:744-750.
 
37. de Brito-Ashurst I, Varagunam M, Raftery MJ, et al. Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol 2009;20:2075-2084.
 
38. Shah SN, Abramowitz M, Hostetter TH, et al. Serum bicarbonate levels and the progression of kidney disease: a cohort study. Am J Kidney Dis 2009;54:270-277.
 
39. Goraya N, Simoni J, Jo CH, et al. Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate. Kidney Int 2014;86:1031-1038.
 
40. Kovesdy CP. Metabolic acidosis and progression of chronic kidney disease. In: Wesson DE, , ed. Metabolic Acidosis: A Guide to Clinical Assessment and Management. New York: Springer; 2016:131-143.
 
41. Brosnahan G, Fraer M. Management of chronic kidney disease: what is the evidence. South Med J 2010;103:222-230.
 
42. Chauhan V, Kelepouris E, Chauhan N, et al. Current concepts and management strategies in chronic kidney disease-mineral and bone disorder. South Med J 2012;105:479-485.
 
43. Bayram D, Tugrul Sezer M, Inal S, et al. The effects of allopurinol on metabolic acidosis and endothelial functions in chronic kidney disease patients. Clin Exp Nephrol 2015;19:443-449.
 
44. Saito J, Matsuzawa Y, Ito H, et al. The alkalizer citrate reduces serum uric acid levels and improves renal function in hyperuricemic patients treated with the xanthine oxidase inhibitor allopurinol. Endocr Res 2010;35:145-154.
 
45. Kimmel PL, Miller G, Mendelson WB. Sleep apnea syndrome in chronic renal disease. Am J Med 1989;86:308-314.
 
46. Fülöp T, Hickson DA, Wyatt SB, et al. Sleep-disordered breathing symptoms among African-Americans in the Jackson Heart Study. Sleep Med 2012;13:1039-1049.
 
47. Sim JJ, Rasgon SA, Kujubu DA, et al. Sleep apnea in early and advanced chronic kidney disease: Kaiser Permanente Southern California cohort. Chest 2009;135:710-716.
 
48. Afshan S, Farah Musa AR, Echols V, et al. Persisting hypocalcemia after surgical parathyroidectomy: the differential effectiveness of calcium citrate versus calcium carbonate with acid suppression. Am J Med Sci 2017;353:82-86.