Febuxostat is superior to traditional urate-lowering agents in reducing the progression of kidney function in chronic kidney disease patients

Figures & data

Figure 1. Flow chart of patient selection.

Table 1. Baseline characteristics of the study population

Characteristics	Non-conversion (n = 2,214)	Conversion (n = 206)	Febuxostat first (n = 40)	p
Age (yrs), mean (SD)	69.9 ± 15.8	63.1 ± 17.4	67.5 ± 15.1	<0.001
Female, n (%)	628 (28.4)	55 (26.7)	14 (35.0)	0.563
Smoking, n (%)	916 (41.4)	80 (38.8)	13 (32.5)	0.601
Comorbidities
Diabetes mellitus, n (%)	790 (35.7)	52 (25.2)	18 (45.0)	0.004
Hypertension, n (%)	1,721 (77.8)	159 (77.2)	29 (72.5)	0.721
Cardiovascular disease, n (%)	254 (11.5)	25 (12.1)	5 (12.5)	0.944
Hepatitis B or C, n (%)	114 (5.2)	15 (7.3)	5 (12.5)	0.116
Hyperlipidemia, n (%)	643 (29.1)	69 (33.5)	7 (17.5)	0.105
Anemia, n (%)	284 (12.8)	31 (15.1)	3 (7.5)	0.389
Gout attack, n (%)	106 (4.8)	4 (1.9)	2 (5.0)	0.447
Malignancy, n (%)	131 (5.9)	15 (7.3)	4 (10.0)	0.430
Abnormal BMI, n (%)	466 (21.1)	43 (20.9)	15 (37.5)	0.042
Systolic BP (mm Hg)	134.0 ± 16.9	133.8 ± 16.8	138.7 ± 21.4	0.464
Diastolic BP (mm Hg)	75.3 ± 11.0	75.5 ± 11.3	79.7 ± 10.4	0.060
eGFR, MDRD (initial)^m	30.6 ± 15.7	32.0 ± 14.1	28.4 ± 19.1	0.113
eGFR, CKD-EPI (initial)^m	34.3 ± 19.4	24.0 ± 14.3	25.4 ± 13.8	0.125
CKD, stages (initial, MDRD equation)				0.289
Stage 1, n (%)	15 (0.7)	1 (0.5)	1 (2.5)
Stage 2, n (%)	68 (3.1)	5 (2.4)	0 (0.0)
Stage 3, n (%)	1,030 (46.5)	108 (52.4)	16 (40.0)
Stage 4, n (%)	719 (32.5)	68 (33.0)	14 (35.0)
Stage 5, n (%)	382 (17.3)	24 (11.7)	9 (22.5)
Laboratory test
Hematocrit (%)	33.5 ± 6.0	33.8 ± 6.7	33.1 ± 6.0	0.617
Albumin (g/dL)	4.0 ± 0.5	4.2 ± 0.5	4.1 ± 0.4	0.049
Proteinuria (mg/day)	730.0 (200.0–1990.0)	810.0 (287.5–2017.5)	515.0 (137.5–3125.0)	0.577
Uric acid (mg/dL)	7.3 ± 2.0	8.7 ± 2.0	9.2 ± 1.6	0.015
Bun (mg/dL)	35.5 ± 19.0	45.9 ± 19.0	33.8 ± 9.6	0.034
Creatinine (mg/dL)	2.5 ± 1.6	3.4 ± 1.7	2.4 ± 0.9	0.001
Duration of drug exposure (years)	2.1 (1.0–3.9)	3.2 (1.4–4.8)	0.5 (0.0–2.5)	<0.001

Notes:

Calculated by Student’s t-test, Pearson χ² test, Fisher’s exact test, and ^mMann-Whitney test. Interquartile range was presented for proteinuria and duration of drug exposure. BMI, body mass index. MDRD: modification of diet in renal disease. CKD-EPI: chronic kidney disease epidemiology collaboration.

Table 2. Characteristics of patients with chronic kidney diseases and hyperuricemia with medications

Medication	Non-conversion (n = 2,214)	Conversion (n = 206)	Febuxostat first (n = 40)	p
Allopurinol (mg/day), mean dose	109.1 ± 33.1 (n = 1,392)	114.3 ± 40.6 (n = 127)		0.221
Benzbromarone & narcaricin (mg/day), mean dose	51.0 ± 7.5 (n = 1,194)	51.9 ± 7.8 (n = 183)		0.015
Colchicine (mg/day), mean dose	0.5 ± 0.1 (n = 880)	0.5 ± 0.1 (n = 154)	0.5 ± 0.0 (n = 2)	0.570
Febuxostat (mg/day), mean dose		43.1 ± 10.1 (n = 206)	43.8 ± 10.7 (n = 40)	0.555

Figure 2. Serial change of laboratory data, including (A) change of median serum uric acid concentration and serum creatinine, and (B) estimated glomerular filtration rate by the Modification of Diet in Renal Disease (MDRD) equation and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.

Figure 3. Decline of estimated glomerular filtration rate before and after urate-lowering agents.

Notes: Our data were mostly calculated by the Wilcoxon sing rank test using values for start drug and after drug. The Friedman test was not used for repetitive three tests in one person. The p-value of the febuxostat group is not shown because of the low power of analysis.

Table 3. Association of baseline variables with end-stage renal disease using multivariable Cox proportional Hazard analysis

	Univariate analysis (n = 2,460)		Multivariate analysis (n = 489)^a
	HR 95% CI	p	HR 95% CI	p
Conversion group	0.82 (0.70–0.95)	0.010	0.51 (0.39–0.69)	<0.001
No conversion group	Reference		Reference
Febuxostat alone or first group	0.97 (0.66–1.43)	0.876	–	–
Age, yr	0.99 (0.99–1.00)	<0.001	0.99 (0.98–1.00)	0.003
Female	1.13 (1.02–1.24)	0.020	0.90 (0.72–1.13)	0.348
Diabetes mellitus	1.23 (1.12–1.35)	<0.001	1.27 (1.00–1.61)	0.050
Hypertension	0.94 (0.84–1.05)	0.262
Cardiovascular disease	1.48 (1.28–1.70)	<0.001	1.20 (0.74–1.95)	0.471
Hyperlipidemia	1.31 (1.18–1.44)	<0.001	1.28 (1.03–1.59)	0.025
Anemia	2.01 (1.75–2.31)	<0.001	1.65 (1.22–2.23)	0.001
Gout attack	2.01 (1.62–2.48)	<0.001	2.16 (1.04–4.48)	0.039
Abnormal BMI	1.27 (1.14–1.43)	<0.001	1.40 (1.10–1.78)	0.007
eGFR, MDRD	0.99 (0.98–0.99)	<0.001	0.98 (0.97–1.00)	0.029
CKD, stages
Stage 2	1.35 (1.04–1.76)	0.024	1.62 (0.90–2.90)	0.105
Stage 3	Reference		Reference
Stage 5	2.58 (2.27–2.94)	<0.001	1.24 (0.68–2.28)	0.479
Hematocrit	0.98 (0.98–0.99)	<0.001	0.99 (0.97–1.01)	0.376
Albumin	0.75 (0.69–0.83)	<0.001	0.84 (0.64–1.11)	0.222
Urine PC ratio	1.00 (1.00–1.00)	0.001	1.00 (1.00–1.00)	0.606
Allopurinol	1.00 (1.00–1.00)	0.294
Benzbromarone	0.99 (0.99–1.00)	0.042	0.99 (0.98–1.00)	0.145
Colchicine	0.50 (0.18–1.39)	0.186
Febuxostat	1.00 (0.99–1.01)	0.987

Notes: HR: hazard ratio; CI: confidence interval; MDRD: modification of diet in renal disease; CKD: chronic kidney disease.

^a Adjusted for the three groups, age, gender, diabetes mellitus, cardiovascular disease, hyperlipidemia, anemia, gout attack, abnormal body mass index (BMI), eGFR, CKD, hematocrit, serum albumin, urine PC ratio, and Benzbromarone.

Table 4. Association of baseline variables with death using multivariable Cox proportional Hazard analysis

	Univariate analysis (n = 2,460)		Multivariate analysis (n = 2,016)^a
	HR 95% CI	p	HR 95% CI	p
Conversion group	0.04 (0.00–0.75)	0.031	–	–
No conversion group	Reference		Reference
Febuxostat alone or first group	0.04 (0.00–452.2)	0.502	–	–
Age, yr	1.08 (1.06–1.10)	<0.001	1.06 (1.03–1.09)	<0.001
Female	0.80 (0.50–1.28)	0.349
Diabetes mellitus	2.45 (1.64–3.66)	<0.001	2.17 (1.33–3.56)	0.002
Hypertension	1.02 (0.63–1.67)	0.930
Malignancy	3.42 (1.94–6.03)	<0.001	4.73 (2.49–8.99)	<0.001
Abnormal BMI	0.75 (0.42–1.35)	0.335
eGFR, MDRD	0.96 (0.95–0.98)	<0.001	0.95 (0.90–1.00)	0.060
CKD, stages
Stage 1	0.00 (0.00–0.00)	0.981	0.00 (0.00–0.00)	0.994
Stage 2	0.00 (0.00–8.51)	0.962	0.00 (0.00–0.00)	0.989
Stage 3	Reference		Reference
Stage 4	2.10 (1.35–3.26)	0.001	0.89 (0.35–2.31)	0.815
Stage 5	2.49 (1.37–4.55)	0.003	1.14 (0.24–5.41)	0.868
Systolic blood presssure	0.99 (0.98–1.01)	0.44 7
Diastolic blood pressure	0.97 (0.95–0.99)	0.014	0.99 (0.97–1.02)	0.661
Hematocrit	0.95 (0.92–0.98)	0.003	1.06 (1.01–1.11)	0.015
Albumin	0.29 (0.21–0.40)	<0.001	0.26 (0.17–0.41)	<0.001
Allopurinol	1.00 (1.00–1.01)	0.370
Benzbromarone	1.01 (0.99–1.04)	0.250
Colchicine	0.46 (0.01–40.60)	0.733
Febuxostat	–	–

Notes: HR: hazard ratio; CI: confidence interval; MDRD: modification of diet in renal disease; CKD: chronic kidney disease.

^a Adjusted for group, age, diabetes mellitus, malignancy, eGFR, CKD, diastolic blood pressure, hematocrit, and serum albumin.