Disparity of serum uric acid threshold for CKD among hypertensive and non-hypertensive individuals

Figures & data

Table 1. Baseline characteristics of population with and without hypertension.

	Hypertension (n = 1639)	Non-Hypertension (n = 2541)	p-value	Propensity Hypertension (n = 1354)	Matched Non-Hypertension (n = 1354)	p-value
Demographics
Age, years	61.8 (8.5)	58.4 (8.2)	<.001	60.8 (8.2)	60.9 (8.4)	.803
Male	724 (44.2)	1191 (46.9)	.087	609 (44.9)	630 (46.4)	.418
Married/cohabitating	1236 (75.4)	2021 (79.5)	<.001	1024 (75.5)	1052 (77.5)	.205
Han Nationality	1499 (91.5)	2380 (93.7)	.007	1238 (91.2)	1276 (94.0)	.005
Rural	1374 (83.9)	2173 (85.6)	.133	1159 (85.4)	1149 (84.7)	.537
Education, years			.013			.852
0	504 (30.8)	688 (27.1)		403 (29.7)	419 (30.9)
1–6	748 (45.6)	1161 (45.7)		629 (46.4)	608 (44.8)
7–9	267 (16.3)	456 (18.0)		226 (16.7)	226 (16.7)
>9	120 (7.3)	236 (9.3)		99 (7.3)	104 (7.7)
History of CVD	324 (19.8)	211 (8.3)	<.001	257 (18.9)	133 (9.8)	<.001
Current smoker			.040			.581
Never	1009 (61.6)	1544 (60.9)		823 (60.7)	825 (60.8)
Ever	147 (9.0)	181 (7.1)		114 (8.4)	100 (7.4)
Current	481 (29.4)	809 (31.9)		420 (31.0)	432 (31.8)
Current drinker			<.001			.706
Never	1156 (70.5)	1639 (64.5)		931 (68.6)	912 (67.2)
Ever	117 (7.1)	225 (8.9)		108 (8.0)	109 (8.0)
Current	366 (22.3)	676 (26.6)		318 (23.4)	336 (24.8)
Physical Examination
BMI (kg/m^2)			<.001			.891
Lean (<18.5)	57 (3.5)	186 (7.4)		56 (4.1)	61 (4.5)
Normal (18.5–23.9)	735 (45.4)	1509 (60.1)		688 (50.7)	695 (51.2)
Overweight (24–27.9)	540 (33.4)	635 (25.3)		445 (32.8)	444 (32.7)
Obesity (≥28.0)	286 (17.7)	182 (7.3)		168 (12.4)	157 (11.6)
Waist circumference, cm	1117 (68.4)	1193 (47.2)	<.001	860 (63.4)	801 (59.0)	.013
≥90 for male or 85 for female
Comorbidities
Systolic BP, mm Hg	147 (20.5)	118.2 (11.7)	<.001	146.6 (20.3)	119.3 (11.7)	<.001
Diastolic BP, mm Hg	83.4 (12.1)	70.3 (9.0)	<.001	83.6 (12.1)	70.3 (8.8)	<.001
Diabetes mellitus	188 (11.5)	135 (5.3)	<.001	111 (8.2)	101 (7.4)	.474
Dyslipidemia	686 (41.9)	876 (34.5)	<.001	558 (41.1)	494 (36.4)	.012
sUA, mg/dL			<.001			<.001
Q1 (males: <4.06; females: <3.28)	338 (20.6)	707 (27.8)		322 (23.7)	355 (26.2)
Q2 (males: 4.06–4.75; females: 3.28–3.86)	376 (22.9)	668 (26.3)		327 (24.1)	352 (25.9)
Q3 (males: 4.76–5.68; females: 3.87–4.57)	412 (25.1)	634 (25.0)		335 (24.7)	344 (25.4)
Q4 (males: >5.68; females: >4.57)	513 (31.3)	532 (20.9)		373 (27.5)	306 (22.6)
Blood tests
sUA (mg/dL)	4.6 (1.3)	4.3 (1.2)	<.001	4.5 (1.3)	4.4 (1.2)	.022
Total cholesterol, mmol/L	197.5 (39.4)	190 (38.1)	<0.001	196.7 (39.6)	193 (39.5)	.015
HDL cholesterol, mmol/L	49.1 (15.0)	52.2 (15.4)	<.001	50 (15.1)	50.4 (14.4)	.408
LDL cholesterol, mmol/L	117.3 (36.2)	113.4 (33.4)	<.001	116.5 (35.7)	116.3 (34.4)	.854
Triglycerides (mg/dL)	153.3 (125.9)	123.9 (98.4)	<.001	148.2 (119.8)	131.1 (101.8)	<.001
HbA1c, %	5.3 (0.9)	5.2 (0.7)	<.001	5.3 (0.8)	5.3 (0.8)	.808
Fasting Glucose	113.3 (41.8)	105.8 (28.8)	<.001	111 (38.0)	107.6 (29.3)	.01
Creatine, mg/dL	0.84 (0.20)	0.81 (0.20)	<.001	0.79 (0.20)	0.77 (0.17)	.02
Medication Use
Antihyperglycemic drugs	88 (5.4)	45 (1.8)	<.001	48 (3.5)	35 (2.6)	.174
Antihypertensive drugs	808 (49.3)	0 (0.0)		638 (47.0)	0 (0.0)
Lipid-lowering drugs	158 (9.6)	68 (2.7)	<.001	120 (8.8)	53 (3.9)	<.001

BMI: body mass index; BP: blood pressure; CKD: chronic kidney disease; CVD: cardiovascular disease; eGFR: estimated glomerular filtration rate; HDL: high-density lipoprotein; LDL: low-density lipoprotein; sUA: serum uric acid. a, sUA levels were categorized into <4.55, 4.55–5.24, 5.25–6.35, >6.35 mg/dL for males and <3.28, 3.28–3.86, 3.87–4.57, >4.57 mg/dL for females in all population; and <4.06, 4.06–4.75, 4.76–5.68, >5.68 mg/dL for males and <3.70, 3.70–3.90, 3.91–5.72, >5.72 mg/dL for females mg/dL; Data are presented as No. (%), mean ± SD or median (IQR); *p values were calculated by using T test or Wilcoxon test for continuous variables and χ² test or fisher exact test for categorical variables.

Table 2. Independent predictors of chronic kidney disease at 4-year follow-up in all and PSM population.

	All population			PSM population
	Unadjusted RR (95% confidence interval)	Fully adjusted RR (95% confidence interval)	Bidirectional RR (95% confidence interval)	Unadjusted RR (95% confidence interval)	Fully adjusted RR (95% confidence interval)	Bidirectional RR (95% confidence interval)
Age, per 5 years increase	1.8 (1.7–2.0)***	1.8 (1.7–2.0)***	1.8 (1.6–1.9)***	1.8 (1.6–2.0)***	1.8 (1.6–2.0)***	1.8 (1.6–1.9)***
Male	1.0 (0.7–1.3)	1.1 (0.7–1.6)		0.9 (0.7–1.2)	1.0 (0.6–1.5)
Married/cohabitating	0.6 (0.5–0.8)***	1.2 (0.8–1.6)		0.7 (0.5–0.9)*	1.3 (0.9–1.9)
Rural	1.6 (1.1–2.1)**	1.2 (0.9–1.8)		1.6 (1.1–2.3)*	1.6 (1.0–2.4)*
Education, years
0	1.00 (ref)	1.00 (ref)		1.00 (ref)	1.00 (ref)
1–6	0.8 (0.6–1.0)	1.1 (0.8–1.6)		0.9 (0.6–1.2)	1.2 (0.8–1.8)
7–9	0.6 (0.4–0.9)**	1.4 (0.9–2.3)		0.6 (0.3–1.0)*	1.2 (0.7–2.3)
>9	0.5 (0.3–0.9)*	0.8 (0.4–1.7)		0.4 (0.2–0.8)**	0.6 (0.2–1.7)
History of CVD	1.7 (1.2–2.3)***	1.2 (0.8–1.7)		1.5 (1.0–2.2)*	1.3 (0.8–2.0)
Current smoker
Never	1.00 (ref)	1.00 (ref)		1.00 (ref)	1.00 (ref)
Ever	1.2 (0.8–1.9)	1.0 (0.6–1.8)		1.0 (0.6–1.8)	0.9 (0.5–1.7)
Current	0.9 (0.7–1.2)	1.0 (0.7–1.5)		1.0 (0.7–1.4)	1.0 (0.6–1.5)
Current drinker
Never	1.00 (ref)	1.00 (ref)		1.00 (ref)	1.00 (ref)
Ever	0.7 (0.4–1.1)	0.9 (0.5–1.6)		0.9 (0.5–1.5)	1.0 (0.5–1.8)
Current	0.8 (0.6–1.1)	0.8 (0.6–1.2)		0.8 (0.6–1.2)	0.7 (0.5–1.1)
BMI (kg/m^2)
Lean (<18.5)	1.00 (ref)	1.00 (ref)		1.00 (ref)	1.00 (ref)
Normal (18.5–23.9)	0.6 (0.4–1.0)*	0.8 (0.5–1.4)		0.4 (0.3–0.8)**	0.7 (0.4–1.3)
Overweight (24–27.9)	0.7 (0.4–1.2)	0.9 (0.5–1.6)		0.4 (0.2–0.7)**	0.7 (0.3–1.6)
Obesity (≥28.0)	1.0 (0.6–1.8)	1.3 (0.7–2.5)		0.4 (0.2–0.8)**	1.0 (0.4–2.3)
WC, ≥90 for male or 85 for female, cm	1.3 (1.0–1.7)*	1.0 (0.7–1.5)		0.9 (0.7–1.2)	1.1 (0.7–1.7)
Hypertension	2.8 (2.2–3.7)***	1.7 (1.3–2.3)***	1.8 (1.4–2.4)***	1.6 (1.2–2.2)**	1.6 (1.1–2.2)	1.6 (1.1–2.2)**
Diabetes mellitus	1.2 (0.8–1.9)	0.8 (0.5–1.4)		0.6 (0.3–1.2)	0.6 (0.3–1.3)
Dyslipidemia	1.1 (0.8–1.4)	0.8 (0.6–1.1)		0.9 (0.7–1.3)	0.9 (0.6–1.2)
sUA, mg/dL^a
Q1 (males: <4.06; females: <3.28)	1.00 (ref)	1.00 (ref)	1.00 (ref)	1.00 (ref)	1.00 (ref)	1.00 (ref)
Q2 (males: 4.06–4.75; females: 3.28–3.86)	2.4 (1.4–4.2)**	1.9 (1.1–3.4)*	1.9 (1.1–3.4)*	2.1 (1.1–4.1)*	2.0 (1.0–3.9)	1.5 (0.8–2.9)
Q3 (males: 4.76–5.68; females: 3.87–4.57)	3.7 (2.2–6.2)***	3.1 (1.8–5.4)***	3.2 (1.8–5.5)**	3.8 (2.0–7.1)**	3.7 (2.0–7.1)***	2.3 (1.3–4.2)**
Q4 (males: >5.68; females: >4.57)	9.0 (5.5–14.8)***	7.0 (4.2–11.7)***	7.1 (4.2–11.8)***	7.7 (4.3–13.9)**	7.4 (4.0–13.7)	5.5 (3.2–9.6)***
Medication Use
Antihyperglycemic drugs	1.5 (0.8–2.7)			1.0 (0.5–1.8)
Antihypertensive drugs	2.7 (2.1–3.5)***			1.8 (1.3–2.5)***
Lipid-lowering drugs	1.3 (0.8–2.1)	0.8 (0.4–1.4)		1.2 (0.7–2.3)	0.8 (0.4–1.6)

Abbreviation: BMI, body mass index; BP, blood pressure; CKD, chronic kidney disease; CVD: cardiovascular disease; eGFR, estimated glomerular filtration rate; sUA, serum uric acid; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PSM, propensity score matching; RR, risk ratio; WC, waist circumference. Fully adjusted for all listed variables in Logistic regression models. a, SUA levels were categorized into <4.55, 4.55–5.24, 5.25–6.35, >6.35 mg/dL for males and <3.28, 3.28–3.86, 3.87–4.57, >4.57 mg/dL for females in all population; and <4.06, 4.06–4.75, 4.76–5.68, >5.68 mg/dL for males and <3.70, 3.70–3.90, 3.91–5.72, >5.72 mg/dL for females mg/dL in PSM population.).

*p < .05; **p < .01; ***p < .001.

Figure 1. Logistic analyses of sUA quartiles and CKD in the hypertension and non-hypertension. (A) sUA quartiles and CKD risk among the hypertensive individuals; (B) sUA quartiles and CKD risk among the non-hypertensive individuals; (C) sUA quartiles and CKD risk among the propensity hypertensive individuals; (D) sUA quartiles and CKD risk among the matched non-hypertensive individuals).

Figure 2. Multiple-adjusted risk ratios and 95% confidence intervals of CKD associated with sUA threshold ((A) risk for CKD by threshold sUA among the hypertensive individuals; (B) risk for CKD by threshold sUA among the non-hypertensive individuals; (C) risk for CKD by threshold sUA among the propensity hypertensive individuals; (D) risk for CKD by threshold sUA among the matched non-hypertensive individuals).

Table 3. Multivariable-adjusted risk ratios of controlled targets for Chronic kidney Disease according to the presence of sUA and hypertension status.

	Incidence of CKD [n (%)]	Age- and sex-adjusted RR	P value	Fully-adjusted RR	P value
All population
Non-hypertension and sUA < 5.58 mg/dL	69 (3.2)	1.00 (ref)		1.00 (ref)
Hypertension and sUA < 4.55 mg/dL	44 (5.0)	1.1 (0.7–1.6)	0.691	1.1 (0.7–1.6)	0.809
Non-hypertension and sUA ≥ 5.58 mg/dL	29 (8.1)	2.6 (1.6–4.3)	<0.001	2.9 (1.8–4.6)	<0.001
Hypertension and sUA ≥ 4.55 mg/dL	123 (16.3)	4.4 (3.2–6.1)	<0.001	4.1 (2.9–5.8)	<0.001
PSM population
Non-hypertension and sUA < 3.98 mg/dL	10 (2.3)	1.00 (ref)		1.00 (ref)
Hypertension and sUA < 3.76 mg/dL	13 (2.6)	1.0 (0.4–2.4)	0.951	1.0 (0.4–2.4)	0.980
Non-hypertension and sUA ≥ 3.98 mg/dL	59 (6.4)	2.7 (1.4–5.5)	0.005	2.7 (1.3–5.4)	0.006
Hypertension and sUA ≥ 3.76 mg/dL	94 (11.1)	5.5 (2.8–11.0)	<0.001	5.4 (2.7–10.7)	<0.001

Abbreviation: sUA, serum uric acid; RR, risk ratio; Fully-adjusted were adjusted age (as continuous), gender, BMI, WHR, diabetes mellitus, smoking status, and alcohol intake.

Figure 3. Hypertension and HUA jointly promote renal inflammation. ((A) representative micrographs show kidney morphology by H&E staining; (B,E) expression level of kidney injury marker KIM-1 is increased in hypertensive patient and hyperuricemia patients, compared to the control group, which was further increased in patients who developed both hypertension and hyperuricemia; (C,F) immunohistochemical staining revealed an increased infiltration of CD68+ macrophage; (D,G) CD4+ T cells in kidney of hyperuricemia patient and HTN patient, respectively, compared to the control group). And were further increased in patients who developed both HTN and HUA. 10 randomly selected fields of each kidney were counted, data are presented as mean ± SD from 10 patients per group, ** p < .010.

Table 4. Baseline characteristics of the individuals stratified by hypertension and hyperuricemia in the Zhongshan Hospital.

	HTN		P value	Non-HTN		P value
	Hyperuricemia	Non-Hyperuricemia		Hyperuricemia	Non-Hyperuricemia
Participants (n)	10	10		10	10
Demographics
Age, years	53.9 ± 7.6	49.1 ± 14.9	0.213	40.7 ± 15.3	35.4 ± 19.1	0.501
Male	9 (88.9)	8 (90.0)	0.937	9 (90.0)	6 (60.0)	0.302
Married status	10 (100.0)	8 (80.0)	0.279	7 (70.0)	5 (50.0)	0.361
Anthropometry parameters
Weight, kg	73.3 ± 4.5	81.9 ± 13.0	0.108	71.6 ± 17.9	68.0 ± 15.5	0.646
Height, cm	170.8 ± 8.0	171.3 ± 5.5	0.894	171.4 ± 12.4	170.5 ± 6.8	0.851
BMI,	25.2 ± 2.0	27.9 ± 3.6	0.061	24.2 ± 4.0	23.2 ± 4.1	0.602
History of disease
HTN	8 (80.0)	10 (100.0)	0.279	0 (0.0)	0 (0.0)	N.A
Diabetes	4 (40.0)	0 (0.0)	0.033	1 (10.0)	0 (0.0)	0.305
Hepatitis	1 (10.0)	0 (0.0)	0.330	1 (10.0)	0 (0.0)	0.305
Tuberculosis	0 (0.0)	0 (0.0)	N.A	0 (0.0)	0 (0.0)	N.A
Blood tests
ALT, U/L	14.0 (8.0–16.0)	15.0 (12.0–20.0)	0.293	16.0 (13.0–21.0)	17.5 (12.0–52.0)	0.483
AST, U/L	14.5 (13.0–22.0)	16.0 (15.0–18.0)	0.493	14.0 (13.0–28.0)	24.5 (15.0–52.0)	0.087
Creatine, mg/dL	268.0 (129.0–337.0)	160.0 (136.0–230.0)	0.094	156.5 (124.0–242.0)	82.5 (64.0–91.0)	0.002
Urea, mg/dL	16.5 (15.9–22.7)	8.4 (5.5–9.1)	0.006	11.1 (6.8–16.2)	5.2 (3.9–6.6)	0.022
eGFR, ml/min/l.73 m^2	36.6 (15.0–54.0)	47.1 (32.1–53.9)	0.204	50.8 (24.8–60.0)	99.4 (71.5–117.2)	0.003
24-h urinary protein, mg/24 h	0.9 (0.2–1.7)	0.5 (0.3–1.3)	0.541	0.5 (0.1–2.3)	2.5 (0.6–8.8)	0.162
HbA1c, %	6.0 (5.3–7.1)	5.4 (5.2–5.8)	0.111	5.1 (4.8–5.8)	4.9 (4.8–6.8)	0.352
Fasting Glucose, mmol/L	8.1 (6.4–11.6)	6.2 (6.0–9.1)	0.322	5.3 (4.9–7.9)	5.5 (5.1–8.5)	0.813
HDL cholesterol, mmol/L	0.8 (0.7–0.8)	0.9 (0.8–1.0)	0.263	0.9 (0.8–1.2)	1.6 (1.5–1.7)	0.009
LDL cholesterol, mmol/L	2.4 (1.3–3.3)	2.8 (2.2–3.0)	0.684	2.4 (1.9–7.3)	4.2 (2.0–6.0)	0.413
Triglycerides (mg/dL)	2.0 (1.4–4.3)	1.7 (1.6–2.4)	0.205	1.7 (1.3–2.9)	1.8 (1.4–2.3)	0.579
Total cholesterol, mmol/L	4.3 (3.9–6.2)	4.3 (3.9–4.8)	0.366	4.4 (3.3–9.8)	6.7 (4.1–8.0)	0.379
Health-related behavior
Smoking status	3 (30.0)	1 (10.0)	0.313	2 (20.0)	2 (20.0)	1.000
Alcohol drinking	3 (30.0)	0 (0.0)	0.073	1 (10.0)	0 (0.0)	0.305
Discharge medications
Aspirin	0 (0.0)	2 (20.0)	0.456	0 (0.0)	0 (0.0)	N.A
Beta-blocker	1 (10.0)	1 (10.0)	1.000	0 (0.0)	0 (0.0)	N.A
Diuretics	0 (0.0)	0 (0.0)	N.A	0 (0.0)	1 (10.0)	1.000
Lipid-lowering drugs	0 (0.0)	0 (0.0)	N.A	0 (0.0)	1 (10.0)	1.000
Calcium channel blockers	3 (30.0)	0 (0.0)	0.210	1 (10.0)	0 (0.0)	1.00
Antihypertensive drugs	5 (50.0)	3 (30.0)	0.648	0 (0.0)	0 (0.0)	N.A
Xanthine oxidase inhibitor	2 (20.0)	0 (0.0)	0.456	1 (10.0)	0 (0.0)	1.000

ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI: body mass index; BP: blood pressure; eGFR: estimated glomerular filtration rate; sUA: serum uric acid; HDL: high-density lipoprotein; HTN: hypertension; LDL: low-density lipoprotein; Data are presented as No. (%), mean ± SD or median (IQR); *p values were calculated by using T test or Wilcoxon test for continuous variables and χ² test or fisher exact test for categorical variable.

Data availability statement

The data underlying this article are available in CHARLS Database at http://charls.pku.edu.cn/.