Observational Study
Copyright ©The Author(s) 2023.
World J Nephrol. Dec 25, 2023; 12(5): 168-181
Published online Dec 25, 2023. doi: 10.5527/wjn.v12.i5.168
Table 1 Demographic information and baseline characteristics of the cohort based on estimated glomerular filtration rate categories
Demographic variables
eGFR ≥ 60, n = 2181
eGFR 45-59, n = 4911
eGFR 30-45, n = 9621
eGFR 15-29, n = 11741
eGFR < 15, n = 3851
Total, n = 32301
P value1
Age, yr53 (44-63)62 (50-70)68 (56-75)70 (60-78)71 (60-78)67 (56-76)< 0.001
Sex, male126 (57.8)308 (62.7)573 (59.6)691 (58.9)251 (65.2)1949 (60.3)0.143
Ethnicity, white198 (90.8)467 (95.1)924 (99.6)1127 (96.0)375 (97.4)3091 (95.7)0.003
BMI, kg/m228.3 (24.6-33.2)28.2 (25.0-32.4)28.0 (25.0-32.4)28.0 (25.0-32.6)27.4 (24.0-33.0)28.0 (24.7-32.6)0.490
Systolic BP, mmHg132 (120-148)135 (122-150)139 (125-153)140 (126-155)143 (130-160)139 (125-154)< 0.001
Diastolic BP, mmHg76 (70-82)76 (68-82)75 (67-81)72 (65-80)75 (66-82)75 (66-81)0.001
Smoking history124 (56.9)300 (61.1)630 (65.5)781 (65.5)255 (66.2)2090 (64.7)0.027
Alcohol history121 (55.5)252 (51.3)465 (48.3)504 (42.9)149 (38.7)1491 (46.2)< 0.001
Hypertension166 (76.1)414 (84.3)862 (89.6)1091 (92.9)362 (94.0)2895 (89.6)< 0.001
Diabetes mellitus37 (17.0)109 (22.2)291 (30.2)456 (38.8)148 (38.4)1041 (32.2)< 0.001
IHD21 (9.6)75 (15.3)221 (23.0)275 (23.4)75 (19.5)667 (20.7)< 0.001
MI14 (6.4)61 (12.4)149 (15.5)199 (17.0)59 (15.3)482 (14.9)0.001
CCF18 (8.3)52 (10.6)169 (17.6)233 (19.8)84 (21.8)556 (17.2)< 0.001
CVA8 (3.7)25 (5.1)75 (7.8)100 (8.5)41 (10.6)249 (7.7)0.004
PVD19 (8.7)47 (9.6)122 (12.7)169 (14.4)58 (15.1)415 (12.8)0.016
COPD32 (14.7)74 (15.1)179 (18.6)219 (18.7)64 (16.6)568 (17.6)0.260
CLD8 (3.7)19 (3.9)30 (3.1)33 (2.8)9 (2.3)99 (3.1)0.683
Malignancy19 (8.7)39 (7.9)109 (11.3)136 (11.6)50 (13.0)353 (10.9)0.094
Laboratory variables
Haemoglobin, g/L134 (121-145)131 (120-141)126 (115-137)120 (110-130)113 (104-122)123 (112-135)< 0.001
Albumin, g/L44 (41-46)43 (41-45)43 (40-45)42 (40-44)42 (39-44)43 (40-45)< 0.001
Corrected calcium, mmol/L2.32 (2.22-2.40)2.33 (2.24-2.41)2.31 (2.23-2.39)2.30 (2.20-2.39)2.28 (2.17-2.37)2.31 (2.22-2.39)< 0.001
Phosphate, mmol/L1.05 (0.91-1.10)1.03 (0.91-1.16)1.07 (0.95-1.21)1.16 (1.02-1.31)1.39 (1.21-1.59)1.12 (0.98-1.29)< 0.001
ALP, U/L71 (57-85)76 (59-97)82 (66-102)86 (69-112)89 (69-111)83 (66-105)< 0.001
uACR, mg/g215.9 (8.3-57.2)21.0 (10.6-60.5)24.0 (11.7 -77.0)43.0 (16.4-132.7)106.5 (44.4-232.6)32.7 (13.4-111.1)< 0.001
1Continuous variables are expressed with the median value (interquartile range). The P values were calculated by the Kruskal Wallis H test. Categorical variables are expressed as numbers (percentage). The P values were calculated by the χ2 test.
2Missing urine albumin-creatinine ratio values for 391 patients.
ALP: Alkaline phosphatase; BMI: Body mass index; BP: Blood pressure; CCF: Congestive cardiac failure; CLD: Chronic liver disease; COPD: Chronic obstructive pulmonary disease; CVA: Cerebrovascular accidents; eGFR: Estimated glomerular filtration rate expressed as mL/min/1.73 m2; IHD: Ischemic heart disease; MI: Myocardial infarction; PVD: Peripheral vascular disease; uACR: Urine albumin-creatinine ratio.
Table 2 Number of patients prescribed each antihypertensive class at baseline, organized by estimated glomerular filtration rate categories at baseline
Antihypertensive class
eGFR>60, n = 2181
eGFR 45-59, n = 4911
eGFR 30-45, n = 9621
eGFR 15-29, n = 11741
eGFR < 15, n = 3851
Total, n = 32301
P value1
None54 (24.8)73 (14.9)97 (10.1)78 (6.6)26 (6.8)328 (10.2)< 0.001
Three or more agents57 (26.1)158 (32.2)397 (41.3)565 (48.1)206 (53.5)1383 (42.8)< 0.001
Diuretic (thiazide and loop)58 (26.6)172 (35.0)441 (45.8)641 (54.6)213 (55.3)1525 (47.2)< 0.001
CCB (dihydropyridine)58 (26.6)149 (30.3)364 (37.8)480 (40.9)205 (53.2)1256 (38.9)< 0.001
CCB (non- dihydropyridine)6 (2.8)11 (2.2)44 (4.6)50 (4.3)23 (6.0)134 (4.1)0.055
Beta-blocker51 (23.4)133 (27.1)324 (33.7)443 (37.7)156 (40.5)1107 (34.3)< 0.001
Alpha-blocker28 (12.8)72 (14.7)186 (19.3)335 (28.5)158 (41.0)779 (24.1)< 0.001
Central agents9 (4.1)15 (3.1)34 (3.5)59 (5.0)33 (8.6)150 (4.6)0.001
Vasodilators2 (0.9)2 (0.4)6 (0.6)13 (1.1)7 (1.8)30 (0.9)0.189
RAS blocker126 (57.8)316 (64.4)616 (64.0)733 (62.4)192 (50.0)1983 (61.4)< 0.001
Dual RAS blockers22 (10.1)34 (7.0)50 (5.2)67 (5.7)14 (31.6)187 (5.8)0.014
Spironolactone/eplerenone7 (3.2)17 (3.5)36 (3.7)44 (3.7)8 (2.1)112 (3.5)0.599
1Absolute number for frequencies (percentage). The P values were calculated by the χ2 test.
CCB: Calcium channel blocker; eGFR: estimated glomerular filtration rate expressed as mL/min/1.73 m2; RAS: Renin angiotensin system.
Table 3 Number of patients prescribed each antihypertensive class at baseline, organised by primary aetiology of chronic kidney disease at baseline
Primary aetiology of CKD
Three or more1
RAS blocker1
Diuretic1
Beta blocker1
Alpha blocker1
CCB (dihydro-pyridine)1
CCB (non-dihydro-pyridine)1
Central agents1
Diabetes, n = 636386 (61)463 (73)416 (65)239 (38)220 (35)281 (44)32 (5)53 (8)
Hypertension, n = 471246 (52)294 (62)245 (52)210 (45)154 (33)222 (47)33 (7)21 (5)
Renovascular disease, n = 256163 (64)142 (56)178 (70)121 (47)92 (36)122 (48)20 (8)27 (11)
Pyelonephritis, n = 20040 (20)102 (51)54 (27)50 (25)23 (12)61 (31)4 (2)3 (2)
ADPKD, n = 19766 (34)149 (76)69 (35)55 (28)40 (20)78 (40)2 (1)6 (3)
Tubulointerstitial nephritis, n = 1169 (8)40 (35)18 (16)27 (23)8 (7)35 (30)3 (3)2 (20)
Glomerulonephritis, n = 375171 (46)305 (81)174 (46)95 (25)73 (20)147 (39)9 (2)21 (6)
Vasculitis, n = 11831 (26)61 (52)34 (29)35 (30)19 (16)40 (34)2 (2)1 (1)
Haematological disease, n = 318 (26)14 (45)9 (29)8 (26)4 (13)7 (23)01 (3)
Other/unknown aetiology, n = 830263 (32)413 (50)328 (40)267 (32)146 (18)263 (32)29 (4)15 (2)
1Absolute number for frequencies (percentages).
ADPKD: Autosomal dominant polycystic kidney disease; CCB: Calcium channel blocker; CKD: Chronic kidney disease; RAS: Renin angiotensin system.
Table 4 Number of patients prescribed with each antihypertensive class at baseline, organized by urine albumin-creatinine ratio categories at baseline
Antihypertensive class
uACR < 30, n = 13551,2
uACR 30-300, n = 12361,2
uACR > 300, n = 2481,2
Total, n = 28391,3
P value1
None148 (10.9)112 (9.1)12 (4.8)272 (9.6)< 0.001
Three or more agents547 (40.4)530 (42.9)155 (62.5)1232 (43.4)< 0.001
Diuretic (thiazide and loop)656 (48.4)542 (43.9)148 (59.7)1346 (47.4)< 0.001
CCB (dihydropyridine)477 (35.2)516 (41.7)122 (49.2)1115 (39.3)< 0.001
CCB (non- dihydropyridine)61 (4.5)54 (4.4)11 (4.4)126 (4.4)0.987
Beta-blocker458 (33.8)418 (33.8)93 (37.5)969 (34.1)0.504
Alpha blocker265 (19.6)335 (27.1)87 (35.1)687 (24.2)< 0.001
Central agent45 (3.3)69 (5.6)23 (9.3)137 (4.8)< 0.001
Vasodilator11 (0.8)16 (1.3)1 (0.4)28 (1.0)0.288
RAS blocker840 (62.0)753 (61.0)174 (70.2)1767 (62.2)0.023
Dual RAS blockers49 (3.6)80 (6.5)41 (16.5)170 (6.0)< 0.001
Spironolactone/eplerenone52 (3.8)29 (2.3)11 (4.4)92 (3.2)0.054
1Absolute number for frequencies (percentages). The P values were calculated by the χ2 test.
2uACR in mg/mg = -0.171 + 0.780 urine protein-creatinine ratio in mg/mg.
3Total was 2839 rather than 3230 as in previous tables as some patients were missing uACR data.
CCB: Calcium channel blocker; RAS: Renin angiotensin system; uACR: Urine albumin-creatinine ratio in mg/g.
Table 5 Number of patients prescribed with each antihypertensive class at baseline, organized by categories according to the prevalence of congestive cardiac failure and other cardiovascular events at baseline
Antihypertensive class
CCF, n = 5561
No CCF, n = 26741
P value1
CVE, n = 18291
No CVE, n = 14011
P value1
None22 (4.0)306 (11.4)< 0.00172 (5.1)256 (14.0)< 0.001
Diuretic (thiazide and loop)381 (68.4)1144 (42.8)< 0.001818 (58.4)707 (38.7)< 0.001
CCB (dihydropyridine)192 (34.5)1064 (39.8)0.021561 (40.0)695 (38.0)0.238
CCB (non-dihydropyridine)32 (5.8)102 (3.8)0.03792 (6.6)42 (2.3)< 0.001
Beta blocker248 (44.6)859 (32.1)< 0.001621 (44.3)486 (26.6)< 0.001
Alpha blocker140 (25.2)639 (23.9)0.520385 (27.5)394 (21.7)< 0.001
Central agent29 (5.2)121 (4.5)0.48173 (5.2)77 (4.2)0.180
Vasodilator4 (0.7)26 (1.0)0.57217 (1.2)13 (0.7)0.140
RAS blocker360 (64.7)1623 (60.7)0.074839 (42.3)1144 (57.7)0.124
Dual RAS blockers24 (4.3)163 (6.1)0.10270 (37.4)117 (62.6)0.091
Spironolactone/eplerenone56 (10.1)56 (2.1)< 0.00180 (5.7)32 (1.7)< 0.001
1Absolute number for frequencies (percentages). The P values were calculated by the χ2 test.
CCB: Calcium channel blocker; CCF: Congestive cardiac failure; CVE: Cardiovascular events; RAS: Renin angiotensin system.
Table 6 Number of patients prescribed with each antihypertensive class at baseline and at the 12-mo follow-up
Antihypertensive class
Baseline, n = 22561
12-mo follow-up, n = 22561
P value1
Diuretic (thiazide and loop)1131 (50.1)1107 (49.1)0.475
CCB (dihydropyridine)905 (40.1)930 (41.2)0.449
CCB (non- dihydropyridine)102 (4.5)90 (4.0)0.376
Beta blocker783 (34.7)767 (34.0)0.616
Alpha blocker544 (24.1)558 (24.7)0.628
Central agent111 (4.9)117 (5.2)0.683
Vasodilator19 (0.8)15 (0.7)0.491
RAS blocker1416 (62.8)1383 (61.3)0.311
Dual RAS blockers145 (6.4)163 (7.2)0.288
Spironolactone/eplerenone84 (3.7)73 (3.2)0.372
1Absolute number for frequencies (percentages). The P values were calculated by the χ2 test.
CCB: Calcium channel blocker, RAS: Renin angiotensin system.
Table 7 Number of patients prescribed with each antihypertensive class at baseline and the 12-mo and 24-mo follow-ups
Antihypertensive class
Baseline, n = 17081
12-mo follow-up, n = 17081
24-mo follow-up, n = 17081
P value1
Diuretic (thiazide and loop)895 (52.4)874 (51.2)839 (49.1)0.153
CCB (dihydropyridine)696 (40.7)710 (41.6)646 (37.8)0.063
CCB (non- dihydropyridine)83 (4.9)74 (4.3)75 (4.4)0.719
Beta blocker588 (34.4)581 (34.0)560 (32.8)0.573
Alpha blocker421 (24.6)433 (25.4)394 (23.1)0.281
Central agent81 (4.7)90 (5.3)66 (5.0)0.779
Vasodilator18 (1.1)14 (0.8)18 (1.1)0.724
RAS blocker1076 (63.0)1077 (63.1)1056 (61.8)0.417
Dual RAS blockers99 (5.8)127 (7.4)122 (7.1)0.127
Spironolactone/eplerenone58 (3.4)49 (2.9)43 (2.5)0.309
1Absolute number for frequencies (percentages). The P values were calculated by the χ2 test.
CCB: Calcium channel blocker, RAS: Renin angiotensin system.
Table 8 Patient proportion achieving blood pressure < 140/90 mmHg at the 12-mo and 24-mo follow-ups in comparison to baseline
Time
Total number of patients
Number of patients with BP < 140/90 mmHg1
P value1
Baseline32301549 (48.0)-
12-mo follow-up20961083 (52.0)0.008
24-mo follow-up1541797 (51.7)0.015
1Absolute number for frequency (percentage). The P values were calculated by the χ2 test.
BP: Blood pressure.
Table 9 Patient proportion achieving blood pressure < 140/90 mmHg at the 12-mo and 24-mo follow-ups in comparison to baseline (patients on three or more antihypertensive agents)
Total number of patients on three or more agents
Number of patients with BP < 140/90 mmHg1
P value1
Baseline1383629 (45.5)-
12-mo follow-up961473 (49.2)0.074
24-mo follow-up724359 (49.6)0.072
1Absolute number for frequency (percentage). The P values were calculated by the χ2 test.
BP: Blood pressure.
Table 10 Cox regression analysis demonstrating associations between the prescription of three or more antihypertensive agents with all-cause mortality
Analysis
HR (95%CI)1
P value1
Univariate model1.55 (1.41-1.69)< 0.001
Multivariate model 121.33 (1.21-1.45)< 0.001
Multivariate model 231.23 (1.12-1.35)< 0.001
Multivariate model 341.15 (1.04-1.27)0.006
1Absolute number for hazard ratio alongside corresponding 95% confidence interval and P value.
2Multivariate model 1: adjusted for age, sex, ethnicity, smoking status, and alcohol intake.
3Multivariate model 2: adjusted for all covariates of model 1 plus diabetes, any cardiovascular disease (ischemic heart disease or myocardial infarction or congestive cardiac failure or cerebrovascular accident or peripheral vascular disease), and blood pressure control < 140/90 mmHg.
4Multivariate model 3: adjusted for all covariates of model 2 plus estimated glomerular filtration rate and urine albumin-creatinine ratio.
HR: Hazard ratio; 95%CI: 95% confidence interval.
Table 11 Cox regression analysis demonstrated associations between the prescription of three or more antihypertensive agents with progression to end stage kidney disease
Analysis
HR (95%CI)1
P value1
Univariate model1.60 (1.39-1.84)< 0.001
Multivariate model 121.81 (1.56-2.10)< 0.001
Multivariate model 231.55 (1.37-1.76)< 0.001
Multivariate model 341.31 (1.14-1.50)< 0.001
1Absolute number for hazard ratio alongside corresponding 95% confidence interval and P value.
2Multivariate model 1: adjusted for age, sex, ethnicity, smoking status, and alcohol intake.
3Multivariate model 2: adjusted for all covariates of model 1 plus diabetes, any cardiovascular disease (ischemic heart disease or myocardial infarction or congestive cardiac failure or cerebrovascular accident or peripheral vascular disease), and blood pressure control < 140/90 mmHg.
4Multivariate model 3: adjusted for all covariates of model 2 plus estimated glomerular filtration rate and urine albumin-creatinine ratio.
HR: Hazard ratio; 95%CI: 95% confidence interval
Table 12 Rate of decline in estimated glomerular filtration rate in patients with three or more antihypertensive agents vs less than three antihypertensive agents prescribed
eGFR
Three or more agents prescribed1
Less than three agents prescribed1
P value1
2Delta eGFR, mL/min/1.73 m2/yr-1.79 (-4.25 to -0.07)-1.07 (-3.10 to 0.72)< 0.001
1Expressed as a median (interquartile range). The P value was calculated by the Mann-Whitney U test.
2Delta estimated glomerular filtration rate analysis included 3068 patients with estimated glomerular filtration rate data available as defined.
eGFR: Estimated glomerular filtration rate.