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

Tibor Fülöp, MD, PhD; Christian A. Koch, MD, PhD, MACE; Lindsey T. Norris, MD; BetzaidaRodríguez, MD; Tibor Szarvas, PhD; Zsolt Lengvárszky, PhD; Éva Csongrádi, MD, PhD; Mehul P. Dixit, MD

Disclosures

South Med J. 2018;111(9):549-555. 

In This Article

Discussion

We worked with data taken from a cohort under treatment; hence, correlates of the allopurinol doses provide a clearer picture of the disease burden of elevated UA than the reported UA levels themselves. The key finding of our study was the relatively poor control of UA in the majority of subjects despite receiving fair doses of allopurinol. The limitations of the study notwithstanding, weight has emerged as a hitherto underappreciated determinant of the empiric allopurinol dose titrated for the subjects. Similarly, BMI was an independent predictor of UA levels, whereas eGFR was not. Furthermore, although serum bicarbonate was under fair control (25 ± 3.2 mEq/L), our study subjects had ongoing urinary acidification (mean urine pH 5.76 ± 0.76) with pH <6 in 60.5% of the cohort. In reviewing the literature, among community-dwelling participants, a study pooling 13,338 subjects from the Atherosclerosis Risks in Communities and the Cardiovascular Health Study with intact kidney function, baseline UA level was associated with a modest increase in risk for incident CKD after adjusting for multiple demographic variables and comorbid illnesses.[12] A more pronounced effect was seen from a large cohort of healthy volunteers (N = 21,475) in Austria, with a rapid increase in CKD risk, with UA >7 mg/dL in women and >8 mg/dL in men.[13] In a cohort of 1449 type 2 diabetics with normal kidney function and without overt proteinuria, the presence of elevated UA roughly doubled the likelihood of new-onset CKD during a 5-year period.[14] The risk persisted after adjustment for age, sex, BMI, smoking status, diabetes mellitus duration, systolic blood pressure, antihypertensive treatment, insulin therapy, HbA1c and baseline eGFR. The effect of a diuretic increasing UA is well known across races; however, at least in African American patients, the β-blocker metoprolol may also may contribute to the elevation of UA.[15]

Present evidence strongly suggests that gout care, including the control of UA levels,[16] is suboptimal in the United States, and obesity with elevated BMI is a risk factor for insufficient control. What we consider normal ranges today are derived from populations with less than ideal health and therefore probably should be decreased.[17] The 2012 guidelines of the American College of Rheumatology emphasize a serum UA target of <6 mg/dL when using urate-lowering medical therapy.[18] In the general population, an allopurinol level of up to 900 mg/day is used to achieve target UA levels.[19] In hemodialysis patients in the United Kingdom, it is common to administer 300 mg after each dialysis, three times per week; however, one dose-finding study already documented that doses of up to 350 mg/day do not reach target UA levels in certain patients.[20]

Limited studies conducted after 2005 suggested the potential benefits of lowering UA levels with allopurinol in order to slow down the progression of CKD[21,22] and potentially that of cardiovascular diseases as well.[21,22] The mechanism is unclear, but the reduction of UA with allopurinol may improve endothelial dysfunction.[23] Nonetheless, the positive findings have not been universally confirmed in all studies. A recent meta-analysis found that the pooled estimate of changes for eGFR was in favor of allopurinol with a mean difference of 3.2 mL · min−1 · 1.73 m2 (95% confidence interval [CI] 0.16–6.2 mL· min−1 · 1.73 m2, P = 0.039) for serum creatinine, along with a reduction of systolic and diastolic blood pressures.[24] Two recent, albeit small trials have since emerged in support our thesis—one from Iran[25] and the other from India.[26] Further, in a retrospective cohort study of male US veterans, the administration of allopurinol over an average of 3.4 years resulted in a significant improvement of kidney function,[27] again suggesting a disproportionate benefit in those with a higher initial eGFR detailed above.

The practice of allopurinol use and dose adjustment calibrated for renal function was designed to avoid allopurinol hypersensitivity attributed to metabolite oxipurinol level buildup in patients with CKD.[28,29] It is not entirely clear whether a perceived resistance to allopurinol would in fact signal an insufficient dosing of allopurinol.[30] An allergic reaction to allopurinol is, nonetheless, predominantly idiosyncratic and not dose related;[31] hence, it is reasonable to increase the dose of allopurinol—once the decision is made to initiate therapy—until the UA level is lowered into the target range. One study of patients with gout from Australia found no relation between allopurinol sensitivity and the applied dose but pointed out suboptimal control of UA when adjusting the allopurinol dose for renal function.[32] Other authors have also found similar results.[33] However, the presence of furosemide administration was indicative of larger allopurinol doses necessary for sufficient control.[33]

Nonetheless, the choice and dosing of medications in renal failure remain debated. The conversion rate between febuxostat and allopurinol remains unclear. A small study of subjects with CKD from Japan suggests a conversion rate of 1:10 (10 mg febuxostat equaling 100 mg of allopurinol) but simultaneously, a greater effect and larger conversion ratio of febuxostat at extremely low eGFR, as well.[34] A study analyzing the Medicare database from 2006–2012 found that allopurinol was associated with a lower risk of incident renal disease than febuxostat in older adult patients and that the risk reduction was progressive with escalating allopurinol doses 0.75 (95% CI 0.65–0.86), 0.61 (95% CI 0.52–0.73), and 0.48 (95% CI 0.41–0.55), for allopurinol doses <200, 200 to 299, and ≥300 mg/day, respectively.[35] Febuxostat, while initially believed to be safer in patients with CKD, may be associated with myopathy at extremely low GFR states.[36]

Both hyperuricemia[6,12–14] and metabolic acidosis[37–39] have emerged as possible risk factors for the progression of kidney disease.[40,41] In the paradigm of CKD care, we are focusing not merely on bone health but on the impact of overall metabolic control in CKD subjects and modifiable risk factors of progression.[42] It is interesting that in a small study, allopurinol not only lowered serum UA (7.9 ± 1.6 to 6.4 ± 1.7, P< 0.001) but also resulted in rise of serum HCO3 (21.4 ± 3.4 to 23.0 ± 3.4, P = 0.007) in the enrollees.[43] Another small study from Japan (N = 56) demonstrated that alkali supplementation (with per os citrate) along with allopurinol was more effective than allopurinol alone in decreasing the UA levels and increasing urine pH (6.1 ± 0.7 vs 6.3 ± 0.6, P = 0.0425) and increasing creatinine clearance (88.2 ± 30 vs 97.2 ± 31.2, P = 0.0350).[44] In our cohort most subjects had ongoing urinary acidification, despite a seemingly satisfactory serum bicarbonate control. One potential explanation for the ongoing urinary acidification, given the context of age, obesity, and ethnicity, is the high risk for underlying sleep-disordered breathing in these subjects.[45–47] Herewith, one would not expect resolution of urinary acidification in subjects with sleep-disordered breathing and stages 4 to 5 CKD, unless the serum bicarbonate pushed above the normal range (26–30 mEq/L) with per os bicarbonate supplementations.

The limitations of our study include the relatively small number of enrollees and the single-center and cross-sectional design. Medication compliance was not verified beyond the information derived from patient charts. We did not collect data on calcium-based phosphorus binders, which, in addition to per sodium bicarbonate supplementation, are known to influence serum bicarbonate.[48] On the other hand, this study offers a look into real-life scenarios within the contemporary settings of the urban US southeast. While serum bicarbonate was usually well controlled, our results have disclosed insufficient UA control and ongoing urine acidification in the majority of the cohort, both representing potentially modifiable risk factors for CKD progression. Larger than usual allopurinol doses were well tolerated and presented no hematologic adverse effects.

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