Nonlinear association between proteinuria levels and the risk of cardiovascular disease events and all-cause mortality among chronic kidney disease patients

Figures & data

Table 1. Baseline characteristics of the study participants according to the urinary protein/creatinine ratio (UPCR).

Variable	Urinary protein/creatinine ratio (UPCR), g/gCr			p Value
	UPCR (<1.0)	UPCR (≥1.0-<3.50)	UPCR (≥3.50)
N	590	234	226
Male, n (%)	423 (71.69)	161 (68.80)	151 (66.81)	0.357
Female, n (%)	167 (28.31)	73 (31.20)	75 (33.19)	0.357
Age, years	68.16 ± 13.69	66.56 ± 13.51	65.90 ± 13.21	0.008
Systolic blood pressure, mmHg	134.84 ± 21.86	142.16 ± 21.01	152.57 ± 22.08	<0.001
Body mass index, kg/m^2	23.62 ± 3.86	23.77 ± 4.03	24.35 ± 4.49	0.087
Hemoglobin, g/dL	12.56 ± 2.18	11.49 ± 2.15	10.89 ± 2.16	<0.001
Serum albumin, g/dL	4.12 ± 0.47	3.81 ± 0.51	3.20 ± 0.64	<0.001
eGFR, mL/min/1.73 m^2	38.55 (25.04-50.49)	22.19 (14.29-34.99)	17.45 (11.03-29.95)	<0.001
Etiology of CKD				<0.001
Diabetic nephropathy, n (%)	65 (11.02)	67 (28.63)	139 (61.50)
Nephrosclerosis, n (%)	311 (52.71)	67 (28.63)	36 (15.93)
Glomerulonephritis, n (%)	89 (15.08)	72 (30.77)	37 (16.37)
Other, n (%)	125 (21.19)	28 (11.97)	14 (6.19)
Hypertension, n (%)	504 (85.42)	223 (95.30)	222 (98.23)	<0.001
Diabetes, n (%)	160 (27.12)	85 (36.32)	151 (66.81)	<0.001
History of CVD, n (%)	137 (23.22)	68 (29.06)	77 (34.07)	0.005
Urinary occult blood, n (%)	137 (23.22)	95 (40.95)	125 (55.31)	<0.001
Use of RAAS inhibitors, n (%)	332 (56.27)	170 (72.65)	167 (73.89)	<0.001
Use of calcium channel blockers, n (%)	228 (38.64)	141 (60.26)	133 (58.85)	<0.001
Use of diuretics, n (%)	151 (25.59)	82 (35.04)	121 (53.54)	<0.001
CKD stage, n (%)				<0.001
2	64 (10.85)	14 (5.98)	12 (5.31)
3	326 (55.25)	63 (26.92)	44 (19.47)
4	159 (26.95)	95 (40.60)	82 (36.28)
5	41 (6.95)	62 (26.50)	88 (38.94)
Development of CVD, n (%)	43 (7.29)	25 (10.68)	45 (19.91)	<0.001
Death, n (%)	31 (5.25)	18 (7.69)	24 (10.62)	0.023
Development of CVD or death, n (%)	70 (11.86)	40 (17.09)	63 (27.88)	<0.001

Continuous variables are presented as the means ± standard deviations and the medians with interquartile ranges. Categorical data are presented as numbers and percentages.

CKD: chronic kidney disease; CVD; cardiovascular disease; eGFR: estimated glomerular filtration rate; UPCR: urinary protein/creatinine ratio; g/gCr: gram per gram creatinine; RAAS: renin-angiotensin aldosterone system

Table 2. Results of univariate analysis.

	Statistics	HR (95% CI)	p Value
Sex
Male	735 (70.00%)	ref
Female	315 (30.00%)	0.83 (0.59, 1.16)	0.273
Age, years	67.32 ± 13.57	1.05 (1.03, 1.07)	<0.0001
Systolic blood pressure, mmHg	140.27 ± 22.82	1.00 (1.00, 1.01)	0.227
Body mass index, kg/m^2	23.81 ± 4.05	0.97 (0.94, 1.02)	0.225
Hemoglobin, g/dL	11.96 ± 2.28	0.76 (0.71, 0.82)	<0.0001
Serum albumin, g/dL	3.85 ± 0.63	0.43 (0.35, 0.52)	<0.0001
eGFR, mL/min/1.73 m^2	32.91 ± 18.80	0.97 (0.96, 0.98)	<0.0001
CKD_stage
2	90 (8.57%)	Ref
3	433 (41.24%)	1.30 (0.59, 2.87)	0.521
4	336 (32.00%)	3.34 (1.54, 7.22)	0.002
5	191 (18.19%)	3.74 (1.65, 8.45)	0.002
UPCR, g/gCr	0.74(0.13-2.85)	1.11 (1.08, 1.15)	<0.0001
Hypertension
0	101 (9.62%)	Ref
1	949 (90.38%)	2.19 (1.12, 4.27)	0.022
Prevalence of CVD
0	768 (73.14%)	Ref
1	282 (26.86%)	3.02 (2.24, 4.08)	<0.0001
Diabetes
0	654 (62.29%)	Ref
1	396 (37.71%)	2.35 (1.74, 3.17)	<0.0001
use of RAASis
0	381 (36.29%)	Ref
1	669 (63.71%)	1.39 (0.99, 1.93)	0.055
Use of CCB
0	548 (52.19%)	Ref
1	502 (47.81%)	0.97 (0.72, 1.31)	0.867
Use of diuretics
0	696 (66.29%)	Ref
1	354 (33.71%)	2.25 (1.67, 3.03)	<0.0001

Continuous variables are presented as the means ± standard deviations and the medians with interquartile ranges. Categorical data are presented as numbers and percentages.

CKD: chronic kidney disease; CVD: cardiovascular disease; eGFR; estimated glomerular filtration rate; UPCR; urinary protein/creatinine ratio; g/gCr; gram per gram creatinine; RAAS: renin angiotensin aldosterone system inhibitors; CCB: calcium channel blockers

Figure 1. The prevalence rate of the study endpoints in the different UPCR groups. CVD: cardiovascular disease; UPCR: urinary protein/creatinine ratio.

Table 3. Multivariable association of the urinary protein/creatinine ratio with the study endpoints.

Outcome	Unadjusted model			Model 1			Model 2
	HR (95% CI)	p Value	p for trend	HR (95% CI)	p Value	p for trend	HR (95% CI)	p Value	p for trend
Development of CVD (n = 113)
UPCR (g/gCr)	1.13 (1.09, 1.18)	<0.0001		1.15 (1.10, 1.20)	<0.0001		1.11 (1.06, 1.17)	0.00003
UPCR (g/gCr) (groups)			<0.0001			<0.0001			<0.0001
<1.0	Ref			Ref			Ref
≥1.0-<3.50	1.74 (1.06, 2.85)	0.02771		1.87 (1.11, 3.14)	0.01836		1.60 (0.94, 2.73)	0.08062
≥3.50	4.08 (2.68, 6.22)	<0.00001		4.62 (2.96, 7.21)	<0.0001		3.05 (1.89, 4.92)	<0.00001
Per SD increase in UPCR	1.48 (1.31, 1.68)	<0.00001		1.56 (1.36, 1.78)	<0.0001		1.40 (1.20, 1.64)	0.00003
Death (n = 73)
UPCR (g/gCr)	1.10 (1.04, 1.16)	0.00101		1.13 (1.07, 1.20)	0.00003		1.12 (1.05, 1.19)	0.00034
UPCR (g/gCr) (groups)			0.00012			<0.00001			0.00006
<1.0	Ref			Ref			Ref
≥1.0-<3.50	1.65 (0.93, 2.96)	0.08997		2.07 (1.11, 3.86)	0.02257		1.87 (0.98, 3.57)	0.05898
≥3.50	2.87 (1.68, 4.90)	0.00012		3.80 (2.14, 6.74)	<0.0001		3.52 (1.91, 6.50)	0.00006
Per SD increase in UPCR	1.35 (1.13, 1.61)	0.00101		1.48 (1.23, 1.78)	0.00003		1.44 (1.18, 1.75)	0.00034
Development of CVD or Death (n = 173)
UPCR (g/gCr)	1.11 (1.08, 1.15)	<0.00001		1.14 (1.10, 1.18)	<0.0001		1.11 (1.07, 1.15)	<0.00001
UPCR (g/gCr) (groups)			<0.00001			<0.00001			<0.00001
<1.0	Ref			Ref			Ref
≥1.0-<3.50	1.67 (1.14, 2.47)	0.00936		1.93 (1.28, 2.91)	0.00174		1.71 (1.12, 2.61)	0.01248
≥3.50	3.37 (2.39, 4.75)	<0.00001		4.12 (2.87, 5.92)	<0.0001		3.07 (2.08, 4.54)	<0.00001
Per SD increase in UPCR	1.42 (1.27, 1.58)	<0.00001		1.52 (1.36, 1.70)	<0.0001		1.40 (1.24, 1.58)	<0.0001

Model 1: Adjusted by sex, age, BMI.

Model 2: Adjusted by sex, age, BMI, eGFR, hypertension, diabetes, prevalence of CVD, and use of RAASi.

BMI: body mass index; CKD: chronic kidney disease; CVD: cardiovascular disease; eGFR: estimated glomerular filtration rate; UPCR: urinary protein/creatinine ratio; RAASi: renin-angiotensin aldosterone system inhibitor; HR: hazard ratio; CI: confidence interval

Figure 2. A nonlinear relationship was observed between UPCR levels and the incidence of the primary outcome. The red line denotes fitted curves, and the blue line represents 95% confidence intervals for the association between UPCR and the primary outcome. Adjusted for sex, age, BMI, eGFR, hypertension, diabetes, the prevalence of CVD, and the use of RAASi.

Figure 3. Multivariable-adjusted Kaplan–Meier plot for the association of the UPCR groups with the incidence of the primary outcome; Kaplan–Meier plot adjusted for sex, age, BMI, eGFR, hypertension, diabetes, the prevalence of CVD, and the use of RAASi.

Table 4. The results of the two-piecewise linear regression model.

	Incident of the composite endpoint *HR (95% CI)	p Value
Fitting model by standard linear regression	1.109 (1.068, 1.153)	<0.0001
Fitting model by two-piecewise linear regression
The inflection point of the UPCR level	3.93
≤3.93 g/g	1.334 (1.184, 1.504)	<0.0001
>3.93 g/g	1.026 (0.957, 1.099)	0.4766
p for log-likelihood ratio test		0.002

*Adjusted for sex, age, BMI, eGFR, hypertension, diabetes, prevalence of CVD, and use of RAASi.

BMI: body mass index; CKD: chronic kidney disease; CVD; cardiovascular disease; eGFR: estimated glomerular filtration rate; UPCR: urinary protein/creatinine ratio; RAASi: renin angiotensin aldosterone system inhibitor; HR: hazard ratio; CI: confidence interval

Figure 4. Subgroup analysis of UPCR and the study endpoints (A. Development of CVD or death; B. Development of CVD; C. Death). Adjusted for sex, age, BMI, eGFR, hypertension, diabetes, the prevalence of CVD, and the use of RAASi.