Acute kidney injury in stable COPD and at exacerbation

Figures & data

Figure 1 Flowchart of participant inclusion.

Abbreviations: CPRD, Clinical Practice Research Datalink; CKD, chronic kidney disease; AKI, acute kidney injury; COPD, chronic obstructive pulmonary disease.

Table 1 Baseline characteristics of all patients with COPD (n=189,561) and incidence AKI (n=1,610)

Baseline patient characteristics	Total at baseline, n (%)	With AKI, n (rate/100,000 py)	Crude rate ratio of AKI (95% CI)	P-valuea	Adjustedb rate ratio of AKI (95% CI)	P-valuea
Sex
Male	90,466 (47.7)	926 (157)	1 (reference)	<0.001	1 (reference)	<0.001
Female	99,095 (52.3)	684 (95)	0.65 (0.59, 0.72)		0.66 (0.60, 0.73)
Age (years)
<50	30,761 (16.2)	30 (14)	1 (reference)	<0.001	1 (reference)	<0.001
50–59	37,538 (19.8)	125 (38)	3.27 (2.20, 4.88)		3.19 (2.14, 4.75)
60–69	49,422 (26.1)	354 (102)	7.43 (5.12, 10.79)		7.14 (4.92, 10.37)
70–79	46,174 (24.4)	640 (219)	15.84 (10.98, 22.84)		15.30 (10.61, 22.06)
80–89	22,822 (12.0)	423 (368)	26.68 (18.43, 38.64)		26.42 (18.25, 38.27)
≥90	2,844 (1.5)	38 (380)	27.52 (17.04, 44.41)		28.66 (17.76, 46.27)
Region
London	20,819 (11.0)	199 (146)	1 (reference)	<0.001	1 (reference)	<0.001
Midlands	31,903 (16.8)	236 (114)	0.78 (0.64, 0.94)		0.77 (0.64, 0.93)
North England	51,093 (27.0)	487 (142)	0.97 (0.83, 1.15)		1.02 (0.86, 1.20)
South England	85,746 (45.2)	688 (120)	0.82 (0.70, 0.96)		0.80 (0.68, 0.93)
Comorbidities
Body mass index
Underweight	5,313 (2.8)	33 (106)	1.29 (0.91, 1.85)	<0.001	1.42 (0.99, 2.02)	<0.001
Normal	76,011 (40.1)	418 (82)	1 (reference)		1 (reference)
Overweight	64,683 (34.1)	592 (134)	1.63 (1.44, 1.85)		1.43 (1.26, 1.63)
Moderately obese	24,846 (13.1)	299 (178)	2.16 (1.87, 2.51)		2.15 (1.85, 2.49)
Severely obese	7,324 (3.9)	123 (251)	3.06 (2.50, 3.74)		3.80 (3.10, 4.65)
Morbidly obese	3,149 (1.7)	55 (264)	3.22 (2.43, 4.26)		5.17 (3.89, 6.86)
Missing	8,138 (4.3)	90 (238)	–		–
COPD severity (GOLD stage)
I	24,507 (12.9)	145 (81)	1 (reference)	<0.001	1 (reference)	<0.001
II	53,697 (28.3)	514 (138)	1.70 (1.41, 2.04)		1.42 (1.18, 1.71)
III	26,626 (14.1)	295 (172)	2.12 (1.74, 2.59)		1.55 (1.27, 1.90)
IV	7,007 (3.7)	51 (126)	1.56 (1.13, 2.14)		1.15 (0.84, 1.59)
Missing	77,724 (41.0)	605 (123)
Hypertension	89,824 (47.4)	1,161 (191)	2.75 (2.47, 3.07)	<0.001	1.89 (1.69, 2.11)	<0.001
Diabetes mellitus	33,042 (17.4)	613 (272)	2.82 (2.55, 3.12)	<0.001	2.50 (2.26, 2.77)	<0.001
Angina	25,291 (13.3)	398 (226)	2.26 (2.02, 2.53)	<0.001	1.48 (1.32, 1.66)	<0.001
Myocardial infarction	16,872 (8.9)	333 (288)	2.90 (2.57, 3.27)	<0.001	1.92 (1.70, 2.17)	<0.001
Atrial fibrillation	22,065 (11.6)	457 (330)	3.20 (2.87, 3.56)	<0.001	1.84 (1.64, 2.05)	<0.001
Heart failure	21,778 (11.5)	652 (537)	6.36 (5.76, 7.03)	<0.001	3.82 (3.44, 4.24)	<0.001
Coronary artery bypass graft	5,305 (2.8)	130 (366)	3.03 (2.53, 3.64)	<0.001	2.13 (1.78, 2.56)	<0.001
Pulmonary hypertension	1,963 (1.0)	45 (416)	3.31 (2.46, 4.46)	<0.001	2.37 (1.76, 3.18)	<0.001
Kidney disease
CKD stage 3–4	35,090 (18.5)	918 (370)	8.95 (7.96, 10.06)	<0.001	5.90 (5.22, 6.67)	<0.001
Renal diseasec	4,835 (2.6)	286 (1,081)	26.16 (22.48, 30.43)		19.67 (16.87, 22.92)
Medications
COPD medications	160,121 (84.5)	1,428 (135)	1.51 (1.29, 1.76)	<0.001	1.38 (1.18, 1.61)	0.001
Antiplatelets	105,831 (55.8)	1,184 (215)	3.59 (3.21, 4.01)	<0.001	2.08 (1.86, 2.34)	<0.001
Antidiabetes medications	23,591 (12.5)	495 (311)	3.06 (2.75, 3.40)	<0.001	2.85 (2.56, 3.17)	<0.001
Beta blockers	61,155 (32.3)	787 (184)	1.85 (1.68, 2.04)	<0.001	1.53 (1.39, 1.69)	<0.001
Diuretics	101,116 (53.3)	1,437 (220)	7.67 (6.55, 8.98)	<0.001	4.72 (4.00, 5.56)	<0.001
ACEi/ARB	79,359 (41.9)	1,155 (217)	3.46 (3.10, 3.86)	<0.001	2.37 (2.12, 2.65)	<0.001
Vasodilators	11,292 (6.0)	43 (53)	0.40 (0.29, 0.54)	<0.001	0.53 (0.39, 0.71)	<0.001
Alpha blockers	7,338 (3.9)	167 (342)	2.87 (2.44, 3.36)	<0.001	2.00 (1.71, 2.35)	<0.001
Inotropes	15,477 (8.2)	398 (444)	4.27 (3.82, 4.79)	<0.001	2.40 (2.14, 2.70)	<0.001
Nitrates	26,114 (13.8)	395 (236)	2.12 (1.89, 2.38)	<0.001	1.59 (1.41, 1.78)	0.002
Calcium channel blockers	58,611 (30.9)	745 (184)	1.81 (1.64, 2.00)	<0.001	1.36 (1.24, 1.51)	0.001
Antiarrhythmic	7,633 (4.0)	182 (384)	3.25 (2.79, 3.80)	<0.001	2.18 (1.87, 2.55)	<0.001
Anticoagulants	21,977 (11.6)	454 (318)	3.07 (2.75, 3.42)	<0.001	2.05 (1.84, 2.29)	<0.001
Lipid lowering	87,747 (46.2)	1,067 (175)	2.09 (1.88, 2.32)	<0.001	1.64 (1.47, 1.82)	<0.001

Notes:

a Adjusted for sex and age group.

b Joint log likelihood test.

c Renal disease as defined by microalbuminuria, proteinuria, or previous AKI admission.

Abbreviations: COPD, chronic obstructive pulmonary disease; AKI, acute kidney injury; py, person-years; CI, confidence interval; GOLD, Global initiative for chronic Obstructive Lung Disease; CKD, chronic kidney disease; ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blocker.

Table 2 Baseline characteristics of patients with COPD exacerbation (n=36,107) and odds ratios for coexistence of AKI (n=704)

Baseline patient characteristics	Total at baseline, n (%)	Concurrent AKI, n (%)	Crude odds ratio (95% CI)	P-valuea	Adjustedb odds ratio (95% CI)	P-valueb
Sex
Male	19,235 (53.3)	427 (2.2)	1 (reference)	<0.001	1 (reference)	<0.001
Female	16,872 (46.7)	277 (1.6)	0.74 (0.63, 0.86)		0.68 (0.58, 0.80)
Age (years)
<50	1,547 (4.3)	6 (0.4)	1 (reference)	<0.001	1 (reference)	0.066
50–59	4,989 (13.8)	37 (0.7)	1.92 (0.81, 4.56)		1.55 (0.65, 3.71)
60–69	10,404 (28.8)	138 (1.3)	3.45 (1.52, 7.83)		1.93 (0.84, 4.45)
70–79	12,496 (34.6)	303 (2.4)	6.38 (2.84, 14.3)		2.28 (0.99, 5.25)
80–89	6,151 (17.0)	202 (3.3)	8.72 (3.86, 19.68)		2.37 (1.02, 5.50)
≥90	520 (1.4)	18 (3.5)	9.21 (3.64, 23.33)		1.88 (0.72, 4.93)
Region
London	3,811 (10.6)	88 (2.3)	1 (reference)	0.005	1 (reference)	0.035
Midlands	5,453 (15.1)	109 (2.0)	0.86 (0.64, 1.15)		0.84 (0.63, 1.13)
North England	12,054 (33.4)	193 (1.6)	0.69 (0.53, 0.89)		0.89 (0.70, 1.14)
South England	14,789 (41.0)	314 (2.1)	0.92 (0.72, 1.17)		0.71 (0.55, 0.92)
Comorbidities
Body mass index
Underweight	1,418 (3.9)	22 (1.6)	0.94 (0.60, 1.46)	<0.001	1.18 (0.75, 1.86)	0.002
Normal	14,296 (39.6)	236 (1.7)	1 (reference)		1 (reference)
Overweight	12,056 (33.4)	221 (1.8)	1.11 (0.92, 1.34)		0.91 (0.76, 1.11)
Moderately obese	4,893 (13.6)	117 (2.4)	1.46 (1.17, 1.83)		1.23 (0.98, 1.55)
Severely obese	1,345 (3.7)	38 (2.8)	1.73 (1.22, 2.45)		1.51 (1.05, 2.17)
Morbidly obese	643 (1.8)	20 (3.1)	1.91 (1.20, 3.04)		2.13 (1.31, 3.46)
Missing	1,456 (4.0)	50 (3.4)	–		–
COPD severity (GOLD stage)
I	3,669 (10.2)	50 (1.4)	1 (reference)	0.239	1 (reference)	0.292
II	13,690 (37.9)	253 (1.9)	1.36 (1.00, 1.85)		1.34 (0.98, 1.83)
III	9,473 (26.2)	165 (1.7)	1.28 (0.93, 1.76)		1.26 (0.91, 1.75)
IV	2,844 (7.9)	50 (1.8)	1.30 (0.87, 1.92)		1.37 (0.91, 2.07)
Missing	6,431 (17.8)	186 (2.9)	–		–
Hypertension	19,517 (54.1)	480 (2.5)	1.84 (1.57, 2.16)	<0.001	1.35 (1.14, 1.59)	<0.001
Diabetes mellitus	8,044 (22.3)	193 (2.4)	1.32 (1.12, 1.57)	0.001	1.17 (0.98, 1.39)	0.083
Angina	7,252 (20.1)	137 (1.9)	0.96 (0.80, 1.16)	0.676	0.74 (0.61, 0.89)	0.002
Myocardial infarction	5,382 (14.9)	118 (2.2)	1.15 (0.94, 1.41)	0.163	0.85 (0.69, 1.05)	0.125
Atrial fibrillation	7,028 (19.5)	186 (2.7)	1.50 (1.27, 1.78)	<0.001	1.08 (0.91, 1.29)	0.382
Heart failure	7,645 (21.2)	258 (3.4)	2.19 (1.88, 2.56)	<0.001	1.27 (1.08, 1.50)	0.004
Coronary artery bypass graft	1,557 (4.3)	32 (2.1)	1.06 (0.74, 1.51)	0.758	0.82 (0.57, 1.19)	0.304
Pulmonary hypertension	942 (2.6)	23 (2.4)	1.27 (0.83, 1.93)	0.270	1.13 (0.73, 1.73)	0.591
CKD (eGFR mL/kg/1.73 m^2)
≥90	6,320 (17.5)	35 (0.6)	1 (reference)	<0.001	1 (reference)	<0.001
60–89	16,885 (46.8)	145 (0.9)	1.56 (1.07, 2.25)		1.31 (0.89, 1.93)
30–59	11,481 (31.8)	341 (3.0)	5.50 (3.88, 7.79)		4.35 (2.96, 6.38)
15–29	1,258 (3.5)	128 (10.2)	20.30 (13.92, 29.72)		15.80 (10.40, 24.01)
<15	163 (0.5)	55 (33.7)	91.45 (57.47, 145.52)		73.74 (44.97, 120.93)
Medications
COPD medications	35,483 (98.3)	679 (1.9)	0.47 (0.31, 0.70)	<0.001	0.54 (0.36, 0.83)	0.005
Antiplatelets	22,338 (61.9)	480 (2.2)	1.33 (1.13, 1.56)	0.001	0.94 (0.79, 1.11)	0.433
Antidiabetes medications	5,683 (15.7)	153 (2.7)	1.50 (1.25, 1.80)	<0.001	1.32 (1.09, 1.59)	0.004
Beta blockers	11,746 (32.5)	274 (2.3)	1.33 (1.14, 1.55)	<0.001	1.09 (0.93, 1.27)	0.304
Diuretics	25,821 (71.5)	616 (2.4)	2.83 (2.26, 3.55)	<0.001	1.59 (1.25, 2.01)	<0.001
ACEi/ARB	19,347 (53.6)	468 (2.4)	1.74 (1.48, 2.03)	<0.001	1.23 (1.05, 1.45)	0.012
Vasodilators	1,730 (4.8)	14 (0.8)	0.40 (0.23, 0.68)	0.001	0.53 (0.31, 0.91)	0.021
Alpha blockers	1,768 (4.9)	59 (3.3)	1.80 (1.38, 2.36)	<0.001	1.20 (0.90, 1.59)	0.218
Inotropes	5,417 (15.0)	161 (3.0)	1.70 (1.42, 2.03)	<0.001	1.19 (0.99, 1.43)	0.068
Nitrates	7,115 (19.7)	129 (1.8)	0.78 (0.64, 0.96)	0.021	0.77 (0.62, 0.95)	0.016
Calcium channel blockers	13,405 (37.1)	312 (2.3)	1.29 (1.05, 1.57)	0.013	1.31 (1.07, 1.61)	0.010
Antiarrhythmic	2,625 (7.3)	60 (2.3)	1.19 (0.91, 1.56)	0.197	0.85 (0.64, 1.11)	0.230
Anticoagulants	6,976 (19.3)	168 (2.4)	1.32 (1.10, 1.57)	0.002	1.03 (0.86, 1.23)	0.768
Lipid lowering	20,962 (58.1)	405 (1.9)	0.98 (0.84, 1.14)	0.775	1.01 (0.86, 1.17)**	0.941

Notes:

a Joint log likelihood test.

b Adjusted for sex, age group, and eGFR.

** Evidence of collinearity with eGFR, adjusted for age and sex only.

Abbreviations: COPD, chronic obstructive pulmonary disease; AKI, acute kidney injury; CI, confidence interval; GOLD, Global initiative for chronic Obstructive Lung Disease; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker.

Table 3 Univariable and multivariable Poisson regression analyses of the association of baseline characteristics with mortality following COPD exacerbation (n=36,107)

Baseline patient characteristics	Deaths, n (rate/1,000 person-years)	Crude rate ratio (95% CI)	P-valuea	Adjustedb rate ratio (95% CI)	P-valueb
Sex
Male	8,102 (151)	1 (reference)	<0.001	1 (reference)	<0.001
Female	6,345 (131)	0.87 (0.84, 0.90)		0.87 (0.84, 0.90)
Age (years)
<50	155 (35)	1 (reference)	<0.001	1 (reference)	<0.001
50–59	910 (58)	1.67 (1.41, 1.98)		1.73 (1.46, 2.05)
60–69	3,291 (103)	2.97 (2.53, 3.49)		3.21 (2.73, 3.77)
70–79	5,831 (166)	4.79 (4.08, 5.62)		5.24 (4.45, 6.17)
80–89	3,864 (274)	7.88 (6.71, 9.25)		8.37 (7.10, 9.88)
≥90	396 (397)	11.44 (9.50, 13.78)		11.69 (9.66, 14.14)
Region
London	1,413 (132)	1 (reference)	<0.001	1 (reference)	<0.001
Midlands	2,164 (146)	1.11 (1.04, 1.19)		1.13 (1.06, 1.21)
North England	5,899 (144)	1.09 (1.03, 1.16)		1.09 (1.03, 1.15)
South England	4,971 (139)	1.05 (0.99, 1.12)		1.13 (1.07, 1.20)
Acute kidney injury	472 (512)	3.71 (3.39, 4.07)	<0.001	2.47 (2.24, 3.73)	<0.001
Body mass index
Underweight	751 (201)	1.37 (1.27, 1.48)	<0.001	1.41 (1.30, 1.52)	<0.001
Normal	5,848 (147)	1 (reference)		1 (reference)
Overweight	4,425 (127)	0.86 (0.83, 0.90)		0.82 (0.79, 0.85)
Moderately obese	1,726 (118)	0.80 (0.76, 0.85)		0.83 (0.78, 0.87)
Severely obese	478 (116)	0.79 (0.72, 0.87)		0.88 (0.80, 0.96)
Morbidly obese	229 (112)	0.76 (0.67, 0.87)		0.99 (0.87, 1.13)
Missing	990 (341)	–		–
COPD severity (GOLD stage)
I	886 (82)	1 (reference)	<0.001	1 (reference)	<0.001
II	4,095 (99)	1.21 (1.13, 1.30)		1.18 (1.10, 1.27)
III	3,983 (140)	1.72 (2.14, 2.52)		1.63 (1.52, 1.75)
IV	1,580 (189)	2.32 (2.14, 2.52)		2.30 (2.11, 2.50)
Missing	3,903 (295)	–		–
Hypertension	7,654 (136)	0.93 (0.90, 0.96)	<0.001	0.82 (0.79, 0.84)	<0.001
Diabetes mellitus	3,058 (122)	0.83 (0.79, 0.86)	<0.001	0.84 (0.81, 0.87)	<0.001
Angina	3,199 (146)	1.04 (1.00, 1.09)	0.030	0.93 (0.90, 0.97)	<0.001
Myocardial infarction	2,613 (168)	1.23 (1.18, 1.28)	<0.001	1.08 (1.03, 1.12)	<0.001
Atrial fibrillation	3,461 (171)	1.27 (1.22, 1.32)	<0.001	1.00 (0.96, 1.04)	0.844
Heart failure	4,394 (212)	1.72 (1.66, 1.78)	<0.001	1.37 (1.32, 1.42)	<0.001
Coronary artery bypass graft	605 (127)	0.89 (0.82, 0.97)	0.007	0.85 (0.78, 0.92)	<0.001
Pulmonary hypertension	567 (207)	1.49 (1.37, 1.62)	<0.001	1.46 (1.34, 1.59)	<0.001
CKD (eGFR in mL/kg/1.73 m^2)
≥90	1,741 (103)	1 (reference)	<0.001	1 (reference)	<0.001
≥60 and <90	5,981 (114)	1.14 (1.08, 1.20)		0.70 (0.66, 0.74)
≥30 and <60	5,763 (181)	1.76 (1.67, 1.86)		0.81 (0.76, 0.86)
≥15 and <30	842 (360)	3.50 (3.23, 3.80)		1.42 (1.30, 1.55)
<15	120 (476)	4.63 (3.85, 5.57)		1.84 (1.67, 2.44)
COPD medications	14,111 (139)	0.45 (0.40, 0.50)	<0.001	0.54 (0.49, 0.60)	<0.001
Antiplatelets	9,421 (145)	1.08 (1.04, 1.11)	<0.001	0.87 (0.84, 0.90)	<0.001
Antidiabetes medications	2,211 (125)	0.87 (0.83, 0.91)	<0.001	0.92 (0.88, 0.96)	<0.001
Beta blockers	4,351 (132)	0.91 (0.88, 0.94)	<0.001	0.89 (0.86, 0.92)	<0.001
Diuretics	11,744 (161)	1.73 (1.66, 1.80)	<0.001	1.29 (1.24, 1.35)	<0.001
ACEi/ARB	7,959 (141)	1.00 (0.97, 1.03)	0.876	0.87 (0.84, 0.90)	<0.001
Vasodilators	439 (83)	0.58 (0.52, 0.63)	<0.001	0.75 (0.68, 0.82)	<0.001
Alpha blockers	773 (160)	1.14 (1.06, 1.22)	0.001	0.99 (0.92, 1.06)	0.730
Inotropes	3,036 (203)	1.55 (1.49, 1.61)	<0.001	1.22 (1.17, 1.27)	<0.001
Nitrates	3,095 (148)	1.06 (1.12, 1.11)	0.002	1.00 (0.96, 1.04)	0.961
Calcium channel blockers	5,091 (130)	0.87 (0.85, 0.91)	<0.001	0.83 (0.80, 0.86)	<0.001
Antiarrhythmic	1,301 (139)	0.66 (0.64, 0.68)	<0.001	0.68 (0.65, 0.70)	<0.001
Anticoagulants	3,156 (153)	1.06 (1.02, 1.11)	0.002	1.13 (1.08, 1.18)	<0.001
Lipid lowering	7,534 (118)	0.87 (0.84, 0.91)	<0.001	0.91 (0.87, 0.95)	<0.001
Time from exacerbation
<6 months		1 (reference)	<0.001	1 (reference)	<0.001
≥6 months		0.020 (0.19, 0.0.21)		0.024 (0.023, 0.025)

Notes:

a Joint log likelihood test.

b Adjusted for sex, age group, and eGFR.

Abbreviations: COPD, chronic obstructive pulmonary disease; CI, confidence interval; GOLD, Global initiative for chronic Obstructive Lung Disease; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker.

Table 4 Multivariable model of mortality following COPD exacerbation (n=36,107)

Variable	Adjusted RR (95% CI)	P-value
<6 months follow-up
AKI	1.80 (1.61, 2.03)	<0.001
≥6 months follow-up
AKI	1.37 (1.16, 1.62)	<0.001
Age at entry in years (Ref <50)
≥50, <60	1.67 (1.41, 1.98)	<0.001
≥60, <70	2.83 (2.41, 3.34)
≥70, <80	4.06 (3.45, 4.78)
≥80, <90	5.41 (4.58, 6.38)
≥90	6.90 (5.70, 8.35)
Sex: female	0.89 (0.86, 0.92)	<0.001
eGFR in mL/kg/1.73 m^2 (Ref ≥90)
≥60 and <90	0.78 (0.74, 0.83)	<0.001
≥30 and <60	0.88 (0.82, 0.93)
≥15 and <30	1.04 (0.95, 1.13)
<15	1.02 (0.84, 1.24)

Abbreviations: COPD, chronic obstructive pulmonary disease; RR, risk ratio; CI, confidence interval; AKI, acute kidney injury; Ref, reference; eGFR, estimated glomerular filtration rate.

Figure 2 Kaplan–Meier survival curve stratified by AKI among patients with a COPD exacerbation (n=36,107).

Abbreviations: AKI, acute kidney injury; COPD, chronic obstructive pulmonary disease.