Effects of sevelamer and calcium-based phosphate binders on uric acid concentrations in patients undergoing hemodialysis :A randomized clinical trial Jay P. Garg, Scott Chasan-Taber, Andrew Blair, Melissa Plone, Juergen Bommer, Paolo Raggi, Glenn M. Chertow Arthritis & Rheumatism 2005;52(1): 정경환선생님 /R1 조용덕

Introduction chronic kidney disease → increased hyperphosphatemia, hyperparathyroidism, and hyperuricemia, hyperuricemia →a serum uric acid concentration >6.5 or 7.0 mg/dl in men and >6.0 mg/dl in women →gout, insulin resistance, dyslipidemia, hypertension and cardiovascular disease

Aim sevelamer VS calcium-based phosphate binders → reduction in serum uric acid concentration induced by sevelamer

PATIENTS AND METHODS Subjects → adult patients (age 19 years) undergoing maintenance hemodialysis → at 15 participating dialysis units (7 in the US, 7 in Germany, and 1 in Austria

Exclusion criteria → serious gastrointestinal disease (including dysphagia, active untreated gastroparesis, severe motility disorder, major intestinal surgery, markedly irregular bowel function), → ethanol or drug dependence or abuse, → active malignancy, → human immunodeficiency virus infection, → vasculitis → very poorly controlled diabetes mellitus or hypertension

Washout (run-in) phase → 2-week washout period all phosphate binders were withheld → hyperphosphatemia (serum phosphorus concentrations >5.5 mg/dl) during the washout period → randomization Randomization → randomly assigned by computer in a 1:1 ratio to receive either sevelamer or calcium. Study design and procedures

Treatment phase → sevelamer (Renagel 800-mg tablets) → in the US received calcium acetate (PhosLo 667-mg tablets). → in Europe received calcium carbonate (Sertuerner 500-mg tablets). → lasted 52 weeks

Results

Baseline clinical characteristics of the study subjects

Changes in concentrations of uric acid and other biochemical markers In sevelamer-treated subjects → the mean change in uric acid concentration was significantly larger (-0.64 mg/dl versus mg/dl; P = 0.03). In Calcium-treated subjects → larger mean changes in levels of serum calcium (0.43 mg/dl versus mg/dl; P < ) and bicarbonate (3.2 mg/dl versus mg/dl; P < 0.001).

uric acid concentration (from baseline to the end of the study) → directly correlated with the changes in BUN level (r = 0.36, P < ) and serum creatinine level (r = 0.25, P = 0.015), → inversely correlated with the change in serum bicarbonate level (r = -0.16, P = 0.03)..

Multivariable analyses The adjusted mean change in serum uric acid concentration → mg/dl versus mg/dl in sevelamer- versus calcium-treated subjects, respectively (P = 0.001)

Mean change in serum uric acid levels by baseline concentrations..

DISCUSSION serum uric acid concentrations and gaut reduced urinary clearance of urate in chronic kidney disease Hyperparathyroidism → hyperuricemia via enhanced urate absorption several studies (Li-Yu et, Yamanaka et al )

serum uric acid concentrations and cardiovascular disease In the Systolic Hypertension in the Elderly Program (SHEP) study, → 7% increase in the cardiovascular event rate per mg/dl increase in baseline serum uric acid concentration post hoc analysis of the Losartan Intervention For Endpoint (LIFE) → a drug-induced reduction in serum uric acid concentration may decrease the risk of cardiovascular disease

sevelamer Higher levels of inorganic phosphates, rather than organic phosphates → associated with higher mortality in patients with ESRD → sevelamer, a nonabsorbed hydrogel, effectively binds inorganic phosphates in the gastrointestinal tract Previous uncontrolled studies of sevelamer in patients undergoing hemodialysis → mean within-group reductions in serum uric acid concentrations of 0.7 mg/dl

Advanced chronic kidney disease, hyperphosphatemia, hyperlipidemia, and hyperuricemia → sevelamer would be an excellent therapeutic choice.

Colchicines → myoneuropathy, multiorgan failure, cardiorespiratory collapse, bone marrow suppression, death in patients with kidney disease → extreme caution in persons with an estimated GFR of <30 ml/minute/1.73 m2 Allopurino → safely in chronic kidney disease → dose adjustments due to impaired clearance of the drug's major active metabolite, oxypurinol

serum uric acid concentrations and arteriosclerosis In the present study, baseline uric acid concentrations → not associated with the extent of vascular calcification hyperuricemia contribution to atherosclerotic and arteriosclerotic vascular disease in chronic kidney disease → not known

limitations of this analysis → there were no estimates of dietary protein or purine intake → the mechanisms by which serum uric acid concentration is reduced by sevelamer are unknown → the change in serum uric acid concentration was not among the primary outcomes of the parent clinical trial → the sample size was insufficient to evaluate a meaningful difference in cardiovascular events or other hard outcomes, such as flares of gout, mortality, and hospitalizations

Conclusion sevelamer vs calcium-based phosphate binders → a significant decrease in serum uric acid concentrations among subjects randomly assigned to receive sevelamer