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Aging and disease    2019, Vol. 10 Issue (6) : 1270-1281     DOI: 10.14336/AD.2019.0216
Orginal Article |
Frailty Predicts an Increased Risk of End-Stage Renal Disease with Risk Competition by Mortality among 165,461 Diabetic Kidney Disease Patients
Chia-Ter Chao1,2, Jui Wang3, Jenq-Wen Huang4, Ding-Cheng Chan5, Kuo-Liong Chien3
1Department of Medicine, National Taiwan University Hospital BeiHu Branch, College of Medicine, National Taiwan University, Taipei, Taiwan
2Geriatric and Community Medicine Research Center, National Taiwan University Hospital BeiHu Branch, Taipei, Taiwan
3Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
4Nephrology division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
5Department of Medicine, National Taiwan University Hospital ChuTung branch, HsinChu county, Taiwan
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Abstract  

To examine the effect of frailty on diabetic kidney disease patients’ risk of progression to end-stage renal disease (ESRD), mortality, and adverse episodes, as whether frailty modifies their risk of developing ESRD and other adverse outcomes remains unclear. We identified 165,461 DKD patients from the Longitudinal Cohort of Diabetes Patients in Taiwan (n=840,000) between 2004 and 2010, classifying them into those without frailty or with 1, 2 and ≥3 frailty components based on a modified version of FRAIL scale. Using Cox proportional hazard regression analysis, we examined the long-term risk of developing ESRD along with their risk of mortality, supplemented by a competing risk analysis against mortality. Among all participants, 66.2% (n=109,586), 27.2% (n=44,986), 5.9% (n=9,799), and 0.7% (n=1090) patients did not have or had 1, 2, and ≥3 frailty components, respectively. After a 4.1-year follow-up, 4.2% patients developed ESRD and 18.5% died. Cox proportional hazard modeling revealed that patients with 1, 2, and ≥3 frailty components had increased risks of developing ESRD (for 1, 2, and ≥3 components, hazard ratio [HR] 1.13, 1.18, and 1.2, respectively) and mortality (HR 1.25, 1.41, and 1.34, respectively), with. 9% and 16% risk elevations for ESRD and mortality per component increase. Competing risk analysis showed that frailty-induced ESRD risk was attenuated partially by mortality in those with moderate frailty. The receipt of palliative care did not attenuate this risk. Frailty increased the risk of ESRD based on a dose-response relationship among DKD patients with risk competition by mortality.

Keywords chronic kidney disease      diabetes mellitus      diabetic kidney disease      dialysis      end-stage renal disease      frailty      frail phenotype     
About author: These authors make contributions equally to this work.
Just Accepted Date: 19 February 2019   Issue Date: 16 November 2019
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Chao Chia-Ter
Wang Jui
Huang Jenq-Wen
Chan Ding-Cheng
Chien Kuo-Liong
Cite this article:   
Chao Chia-Ter,Wang Jui,Huang Jenq-Wen, et al. Frailty Predicts an Increased Risk of End-Stage Renal Disease with Risk Competition by Mortality among 165,461 Diabetic Kidney Disease Patients[J]. Aging and disease, 2019, 10(6): 1270-1281.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2019.0216     OR     http://www.aginganddisease.org/EN/Y2019/V10/I6/1270
Figure 1.  Algorithm of patient selection and analysis in this study. CKD, chronic kidney disease.
Numbers of frailty component
p-value
0 (n=109,586)1 (n=44,986)2 (n=9,799)≥ 3 (n=1090)
Demographic profile

Age (years)58.1 ± 13.767.1 ± 1473 ± 11.977.5 ± 10.9< 0.001
Sex (Female)48,330 (44.1)20,814 (46.3)4,756 (48.5)509 (46.7)< 0.001
Smoking (%)568 (0.5)282 (0.6)63 (0.6)6 (0.6)0.04
Alcoholism (%)1,173 (1.1)569 (1.3)124 (1.3)16 (1.5)0.004

Duration of CKD (years)2.4 ± 3.32.6 ± 3.22.8 ± 3.32.8 ± 3.2< 0.001

< 162,106 (56.7)22,684 (50.4)4,603 (47)505 (46.3)< 0.001
1 - 311,734 (10.7)5,746 (12.8)1,269 (13)148 (13.6)
3 - 510,849 (9.9)5,873 (13.1)1,418 (14.5)177 (16.2)
≥ 524,897 (22.7)10,683 (23.8)2,509 (25.6)260 (23.9)

Comorbidity profile

CCI1.5 ± 1.63.1 ± 2.44.4 ± 2.55.3 ± 2.5< 0.001
aDCSI0.4 ± 0.80.9 ± 1.21.2 ± 1.41.5 ± 1.5< 0.001
Obesity (%)1,240 (1.1)473 (1.1)86 (0.9)2 (0.2)0.002
Hypertension (%)59,617 (54.4)35,160 (78.2)8,908 (90.9)994 (91.2)< 0.001
Hyperlipidemia (%)36,143 (33)16,844 (37.4)3,659 (37.3)282 (25.9)< 0.001
Chronic liver disease (%)27,047 (24.7)14,120 (31.4)3,452 (35.2)413 (37.9)< 0.001
COPD (%)5,126 (4.7)11,942 (26.6)4,340 (44.3)620 (56.9)< 0.001
Atrial fibrillation (%)7,974 (7.3)9,457 (21)3,069 (31.3)445 (40.8)< 0.001
Acute coronary syndrome (%)16,009 (14.6)16,930 (37.6)5,233 (53.4)629 (57.7)< 0.001
Cerebrovascular disease (%)10,260 (9.4)15,415 (34.3)5,169 (52.8)743 (68.2)< 0.001
Peripheral vascular disease (%)1,919 (1.8)1,813 (4)596 (6.1)82 (7.5)< 0.001
Malignancy (%)6,438 (5.9)6,877 (15.3)2,035 (20.8)243 (22.3)< 0.001
Parkinsonism (%)1,206 (1.1)1,910 (4.3)839 (8.6)193 (17.7)< 0.001
Gout (%)20,837 (19)12,032 (26.8)2,895 (29.5)311 (28.5)< 0.001
Osteoarthritis (any site) (%)22,031 (20.1)17,135 (38.1)5,183 (52.9)635 (58.3)< 0.001
Osteoporosis (%)6,447 (5.9)5,807 (12.9)1,932 (19.7)261 (23.9)< 0.001
Proteinuria (%)1768 (1.6)738 (1.6)170 (1.7)21 (1.9)0.684
Stage 5 CKD (%)187 (0.2)112 (0.3)28 (0.2)2 (0.2)< 0.001

Treatment with adverse renal influences

Cardiac catheterization (%)2,499 (2.3)3,856 (8.6)1,099 (11.2)88 (8.1)< 0.001
Cardiac surgery (any) (%)1,203 (1.1)2,060 (4.6)542 (5.5)39 (3.6)< 0.001

Medications

Aspirin (%)34,212 (31.2)24,728 (55)6,870 (70.1)780 (71.6)< 0.001
β-blockers (%)52,826 (48.2)29,747 (66.1)7,346 (75)766 (70.3)< 0.001
ACEi (%)36,704 (33.5)22,420 (49.8)6,001 (61.2)619 (56.8)< 0.001
ARB (%)28,749 (26.2)18,123 (40.3)4,725 (48.2)486 (44.6)< 0.001
Clopidogrel (%)2,379 (2.2)3,920 (8.7)1,241 (12.7)118 (10.8)< 0.001
Statin (%)29,006 (26.5)13,784 (30.6)3,032 (30.9)237 (21.7)< 0.001
Fibrate (%)16,093 (14.7)7,519 (16.7)1,626 (16.6)126 (11.6)< 0.001
NSAID (any) (%)105,288 (96.1)44,411 (98.7)9,725 (99.2)1,079 (99)< 0.001
Allopurinol (%)4,880 (4.5)3,248 (7.2)849 (8.7)75 (6.9)< 0.001
Warfarin (%)1,235 (1.1)1,755 (3.9)514 (5.3)56 (5.1)< 0.001
Benzodiazepine (%)66,928 (61.1)35,376 (78.6)8,503 (86.8)968 (88.8)< 0.001
Anti-depressants (%)20,050 (18.3)14,227 (31.6)4,198 (42.8)544 (49.9)< 0.001
Anti-psychotics (%)29,734 (27.1)18,772 (41.7)5,492 (56.1)705 (64.7)< 0.001

Oral anti-diabetic agents

Biguanide (%)36,531 (33.3)11,948 (26.6)2,200 (22.5)196 (18)< 0.001
Sulfonylurea (%)36,973 (33.7)12,232 (27.2)2,296 (23.4)193 (17.7)< 0.001
Meglitinide (%)4,563 (4.2)1,843 (4.1)389 (4)33 (3)0.219
α-glucosidase inhibitor (%)5,814 (5.3)2,246 (5)415 (4.2)32 (2.9)< 0.001
Thiazolidinedione (%)3,852 (3.5)1,202 (2.7)195 (2)13 (1.2)< 0.001
DPP4 inhibitors (%)816 (0.7)256 (0.6)60 (0.6)1 (0.1)< 0.001
Insulin (%)6,618 (6)3,073 (6.8)761 (7.8)83 (7.6)< 0.001
Table 1  Comparison of participants without and with different severities of frailty at study enrollment.
Figure 2.  ESRD and chronic dialysis-free survival curves based on frailty status of patients with DKD. DKD, diabetic kidney disease; ESRD, end-stage renal disease
Numbers of frailty component
1
(n = 44,986)
2
(n = 9,799)
≥ 3
(n = 1090)
Components of FRAIL

Fatigue17,030 (37.9)7,801 (79.6)984 (90.3)
Resistance799 (1.8)769 (7.9)363 (33.3)
Ambulation355 (0.8)559 (5.7)286 (26.2)
Illness25,697 (57.1)9,022 (92.1)1,068 (98)
Loss of weight1,105 (2.5)1,447 (14.8)641 (58.8)
Table 2  The distribution of FRAIL component among participants with identified frailty.
Figure 3.  Kaplan-Meier analyses based on the secondary endpoints. Overall (A), cardiovascular event-free (B), hospitalization-free (C), and ICU-free (D) survival curves based on frailty status of patients with DKD. CV, cardiovascular; DKD, diabetic kidney disease; ICU, intensive care unit
OutcomesEventPYID*Crude
Model 1%
Model 2#
Model 3&
Competing risk
HR95% CIHR95% CIHR95% CIHR95% CIHR95% CI
Entering chronic dialysis

Frailty component count

04,107479,967.28.61-1-1-1-1-
12,261165,463.913.71.571.49-1.65a1.131.06-1.2b1.141.07-1.22a1.141.07-1.22a1.091.03-1.16b
253529,994.117.821.82-2.19a1.181.06-1.3b1.21.09-1.34b1.21.08-1.33b1.070.96-1.19
≥ 3562,686.820.82.271.74-2.95a1.20.91-1.571.220.93-1.61.20.91-1.570.970.72-1.31
Every 1 component1.441.4-1.49a1.091.05-1.14a1.11.06-1.15a1.11.05-1.15a1.040.99-1.09

Mortality
FRAIL component count
012,583487,396.925.81-1-1-1-
113,032168,415.577.42.92.83-2.97a1.251.21-1.29a1.261.22-1.3a1.261.22-1.3a
24,33030,562.4141.75.094.92-5.27a1.411.35-1.47a1.421.36-1.48a1.421.36-1.48a
≥ 36612,729242.28.194.57-8.86a1.341.23-1.46a1.351.24-1.47a1.351.24-1.47a
Every 1 component2.242.21-2.27a1.161.14-1.18a1.161.14-1.19a1.161.14-1.19a

Cardiovascular events

FRAIL component count

011,582459,72325.21-1-1-1-
110,974144,045.676.22.92.83-2.98a1.41.35-1.44a1.411.36-1.45a1.411.36-1.45a
23,07424,222.2126.94.614.43-4.8a1.481.41-1.55a1.491.43-1.57a1.491.43-1.57a
≥ 33862,050.8188.26.425.8-7.1a1.551.39-1.7a1.571.41-1.74a1.561.41-1.74a
Every 1 component2.182.15-2.21a1.221.2-1.25a1.231.2-1.25a1.231.2-1.25a

Hospitalization

FRAIL component count

056,620310,452.3182.41-1-1-1-
130,47883,907.9363.21.811.78-1.83a1.171.15-1.19a1.181.16-1.19a1.181.16-1.19a
27,55611,834.1638.52.82.73-2.87a1.281.24-1.31a1.291.25-1.32a1.291.25-1.32a
≥ 3905843.81072.64.043.78-4.32a1.361.27-1.46a1.381.28-1.47a1.381.28-1.47a
Every 1 component1.71.68-1.71a1.141.12-1.15a1.141.13-1.15a1.141.13-1.15a

ICU admission

FRAIL component count

014,369460,577.731.21-1-1-1-
111,970149,386.780.12.482.42-2.54a1.261.22-1.3a1.271.23-1.31a1.271.23-1.31a
23,51325,638.91374.073.93-4.23a1.371.31-1.43a1.381.33-1.45a1.381.33-1.45a
≥ 34832,163.1223.36.265.72-6.86a1.371.25-1.51a1.391.26-1.53a1.391.26-1.53a
Every 1 component2.052.02-2.08a1.171.14-1.19a1.171.15-1.19a1.171.15-1.19a
Table 3  Cox proportional hazard regression with primary and secondary outcomes.
OutcomesEventP-YID*Crude
Model 1%
Model 2#
Model 3&
HR95% CIHR95% CIHR95% CIHR95% CI
Receiving palliative care

FRAIL component count

0556487,309.91.141-1-1-1-
1405168,349.22.412.081.83-2.36a0.990.85-1.1510.85-1.1610.85-1.16
211930,535.73.93.292.7-4.01a1.120.89-1.421.140.9-1.431.140.9-1.43
≥ 382,727.32.932.381.18-4.78c0.60.29-1.230.60.29-1.230.60.29-1.23
Every 1 component1.781.64-1.92a10.9-1.111.010.91-1.121.010.91-1.12
Table 4  Cox proportional hazard regression with receiving palliative care as the dependent variable.
Figure 4.  An illustrative diagram showing the inter-relationship between different severities of frailty and the risk of ESRD and mortality based on findings of this study. DKD, diabetic kidney disease; ESRD, end-stage renal disease
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