Exercise intensity and the risk of end-stage renal disease in diabetes: A nationwide population-based study

Table 1 Baseline characteristics of subjects according to the incident end-stage renal disease

Variable	None ESRD (n = 2471672)	ESRD (n = 23359)	P value	Variable	None ESRD (n = 2471672)	ESRD (n = 23359)	P value
Age	59.56 ± 12	63.43 ± 11.4	0.0001	DM duration			0.0001
Age group			0.0001	New onset	720322 (29.14)	1909 (8.17)
< 40	120544 (4.88)	542 (2.32)		< 5 years	674433 (27.29)	2604 (11.15)
40-64	1502637 (60.79)	11435 (48.95)		5-9 years	485967 (19.66)	3978 (17.03)
≥ 65	848491 (34.33)	11382 (48.73)		≥ 10 years	590950 (23.91)	14868 (63.65)
Sex male (%)	1486398 (60.14%)	15637 (66.94%)	0.0001	BMI (kg/m2)	25.34 ± 3.54	25 ± 3.67	0.0001
Low income1	530489 (21.46)	5878 (25.16)	0.0001	BMI_5 level			0.0001
Smoking			0.0001	< 18.5	33269 (1.35)	477 (2.04)
Never	1360211 (55.03)	12376 (52.98)		18.5-23	575343 (23.28)	6379 (27.31)
Ex-	553739 (22.4)	5820 (24.92)		23-25	597529 (24.18)	5557 (23.79)
Current	557722 (22.56)	5163 (22.1)		25-30	1032471 (41.77)	8857 (37.92)
Drinking			0.0001	≥ 30	233060 (9.43)	2089 (8.94)
None	1423230 (57.58)	16532 (70.77)		WC cm	86.15 ± 8.98	87.08 ± 9.54	0.0001
Moderate	822332 (33.27)	5590 (23.93)		WC level (M/F)			0.0001
Heavy2	226110 (9.15)	1237 (5.3)		< 80/75	361141 (14.61)	3633 (15.55)
Regular exercise	537065 (21.73)	4437 (18.99)	0.0001	< 85/80	489684 (19.81)	4167 (17.84)
Hypertension	1424600 (57.64)	20241 (86.65)	0.0001	< 90/85	604127 (24.44)	5045 (21.6)
Dyslipidemia	1411286 (57.1)	16770 (71.79)	0.0001	< 95/90	485423 (19.64)	4660 (19.95)
CKD3	223756 (9.05)	16054 (68.73)	0.0001	< 100/95	291335 (11.79)	2911 (12.46)
Proteinuria	156756 (6.34)	13927 (59.62)	0.0001	≥ 100/95	239962 (9.71)	2943 (12.6)
SBP (mmHg)	128.4 ± 14.99	134.66 ± 18.01	0.0001	FBS mg/dL	144.46 ± 45.34	156.02 ± 74.42	0.0001
DBP (mmHg)	78.08 ± 9.94	78.17 ± 11.13	0.0001	TC mg/dL	185.3 ± 43.63	181.57 ± 51.26	0.0001
DM medication	1751350 (70.86)	21450 (91.83)	0.0001	HDL-C mg/dL	51 ± 14.71	46.97 ± 14.97	0.0001
OHA ≥ 3	578752 (23.42)	8376 (35.86)	0.0001	LDL-C mg/dL	103.17 ± 38.36	99.19 ± 42.32	0.0001
Metformin	1598169 (64.66)	14570 (62.37)	0.0001	eGFR	89.81 ± 52.98	52.22 ± 40.69	0.0001
SGLT-2 inhibitor	65835 (2.66)	567 (2.43)	0.0256	TG (mg/dL)4	137.57 (137.47-137.66)	155.88 (154.77-157.01)	0.0001

¹Low income 25%.

²Alcohol consumptions ≥ 30 g/day.

³Estimated glomerular filtration rate < 60 mL/min/1.73 m² using MDRD formula.

⁴Geometric mean (95% confidential interval).

CKD: Chronic kidney disease; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; DM: Diabetes mellitus; OHA: Oral hypoglycemic agents; SGLT: Sodium-glucose cotransporter; BMI: Body mass index; WC: Waist circumference; FBS: Fasting blood glucose; TC: Total cholesterol; HDL: High density lipoprotein; LDL: Low density lipoprotein; GFR: Estimated glomerular filtration rate (mL/min/1.73 m²) using MDRD formula; TG: Triglyceride; eGFR: Estimated glomerular filtration rate.

Table 2 Baseline characteristics of study population by diabetes mellitus duration

Variables	New onset (n = 722231)	< 5 years (n = 677037)	5-9 years (n = 489945)	≥ 10 years (n = 605818)	P value
Age	53.72 ± 12.36	58.75 ± 11.32	62.09 ± 10.54	65.53 ± 9.77	< 0.0001
Age group					< 0.0001
< 40	85092 (11.78)	26721 (3.95)	6488 (1.32)	2785 (0.46)
40-64	504540 (69.86)	446861 (66)	286658 (58.51)	276013 (45.56)
≥ 65	132599 (18.36)	203455 (30.05)	196799 (40.17)	327020 (53.98)
Sex male (%)	501523 (69.44)	388124 (57.33)	277851 (56.71)	334537 (55.22)	< 0.0001
Low income1	149558 (20.71)	148265 (21.9)	111167 (22.69)	127377 (21.03)	< 0.0001
Smoking					< 0.0001
Never	337007 (46.66)	377005 (55.68)	283606 (57.89)	374969 (61.89)
Ex-	163967 (22.7)	150191 (22.18)	110089 (22.47)	135312 (22.34)
Current	221257 (30.64)	149841 (22.13)	96250 (19.65)	95537 (15.77)
Drinking					< 0.0001
None	306986 (42.51)	404179 (59.7)	309644 (63.2)	418953 (69.15)
Moderate	318767 (44.14)	214381 (31.66)	143223 (29.23)	151551 (25.02)
Heavy2	96478 (13.36)	58477 (8.64)	37078 (7.57)	35314 (5.83)
Regular exercise	147260 (20.39)	141581 (20.91)	109065 (22.26)	143596 (23.7)	< 0.0001
Hypertension	318886 (44.15)	396558 (58.57)	316466 (64.59)	412931 (68.16)	< 0.0001
Dyslipidemia	258643 (35.81)	447804 (66.14)	322958 (65.92)	398651 (65.8)	< 0.0001
CKD3	33398 (4.62)	45686 (6.75)	51080 (10.43)	109646 (18.1)	< 0.0001
Proteinuria	38161 (5.28)	37292 (5.51)	31993 (6.53)	63237 (10.44)	< 0.0001
SBP (mmHg)	129.44 ± 15.27	127.7 ± 14.66	127.98 ± 14.77	128.5 ± 15.3	< 0.0001
DBP (mmHg)	80.31 ± 10.31	78.36 ± 9.68	77.3 ± 9.48	75.73 ± 9.57	< 0.0001
DM medication	None	677037 (100)	489945 (100)	605818 (100)	< 0.0001
OHA ≥ 3	None	122456 (18.09)	166263 (33.94)	296615 (48.96)	< 0.0001
Metformin	None	621307 (91.77)	443228 (90.46)	540323 (89.19)	< 0.0001
SGLT-2 inhibitor	None	26509 (3.92)	16904 (3.45)	22732 (3.75)	< 0.0001
BMI (kg/m2)	25.59 ± 3.71	25.77 ± 3.61	25.29 ± 3.4	24.57 ± 3.23	< 0.0001
BMI-level					< 0.0001
< 18.5	10909 (1.51)	6977 (1.03)	5778 (1.18)	10082 (1.66)
18.5-23	154876 (21.44)	132903 (19.63)	113133 (23.09)	180810 (29.85)
23-25	163960 (22.7)	156199 (23.07)	122022 (24.91)	160905 (26.56)
25-30	311871 (43.18)	302572 (44.69)	206796 (42.21)	220089 (36.33)
≥ 30	80615 (11.16)	78386 (11.58)	42216 (8.62)	33932 (5.6)
WC (cm)	22.87 ± 3.19	24.27 ± 3.24	25.18 ± 3.34	25.71 ± 4.75	< 0.0001
WC level (M/F)					< 0.0001
< 80/75	119073 (16.49)	84582 (12.49)	65915 (13.45)	95204 (15.71)
< 85/80	147428 (20.41)	125227 (18.5)	94982 (19.39)	126214 (20.83)
< 90/85	173565 (24.03)	164474 (24.29)	120917 (24.68)	150216 (24.8)
< 95/90	136216 (18.86)	138283 (20.42)	99184 (20.24)	116400 (19.21)
< 100/95	79117 (10.95)	87794 (12.97)	60251 (12.3)	67084 (11.07)
≥ 100/95	66832 (9.25)	76677 (11.33)	48696 (9.94)	50700 (8.37)
FBS (mg/dL)	151.55 ± 39.14	137.74 ± 46.25	140.25 ± 45.05	147.38 ± 51.13	< 0.0001
TC (mg/dL)	207.12 ± 41.98	184.24 ± 43.26	174.27 ± 39.29	169.26 ± 38.74	< 0.0001
HDL-C (mg/dL)	52.62 ± 16.28	50.62 ± 14.18	50.34 ± 13.73	49.88 ± 13.92	< 0.0001
LDL-C (mg/dL)	119.45 ± 38.36	102.28 ± 38.38	94.54 ± 35.01	91.57 ± 34.23	< 0.0001
eGFR	93.6 ± 59.94	91.59 ± 51.48	88.39 ± 49.71	83 ± 47.49	< 0.0001
TG (mg/dL)4	156.25 (156.03-156.46)	139.11 (138.93-139.29)	130.23 (130.03-130.42)	122.61 (122.44-122.77)	< 0.0001

¹Low income 25%.

²Alcohol consumptions ≥ 30 g/day.

³Estimated glomerular filtration rate < 60 mL/min/1.73 m² using MDRD formula.

⁴Geometric mean (95% confidential interval).

CKD: Chronic kidney disease; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; DM: Diabetes mellitus; OHA: Oral hypoglycemic agents; SGLT: Sodium-glucose cotransporter; BMI: Body mass index; WC: Waist circumference; FBS: Fasting blood glucose; TC: Total cholesterol; HDL: High density lipoprotein; LDL: Low density lipoprotein; TG: Triglyceride; eGFR: Estimated glomerular filtration rate.

Table 3 Baseline characteristics of study population by exercise intensity

Variables/MET (min/week)	0 (n = 572290)	1-499 (n = 705215)	500-999 (n = 731798)	1000-1499 (n = 310973)	≥ 1500 (n = 174755)	P value
Age	61.55 ± 12.18	58.61 ± 12.17	59.06 ± 12.02	58.74 ± 11.3	60.93 ± 10.86	< 0.0001
Age group						< 0.0001
< 40	20308 (3.55)	39493 (5.6)	40420 (5.52)	15084 (4.85)	5781 (3.31)
40-64	324181 (56.65)	443248 (62.85)	446531 (61.02)	198691 (63.89)	101421 (58.04)
≥ 65	227801 (39.81)	222474 (31.55)	244847 (33.46)	97198 (31.26)	67553 (38.66)
Sex male (%)	302373 (52.84)	411840 (58.4)	459889 (62.84)	207056 (66.58)	120877 (69.17)	< 0.0001
Low income1	135748 (23.72)	149801 (21.24)	152920 (20.9)	62674 (20.15)	35224 (20.16)	< 0.0001
Smoking						< 0.0001
Never	354678 (61.98)	388019 (55.02)	382636 (52.29)	156832 (50.43)	90422 (51.74)
Ex-	87965 (15.37)	150711 (21.37)	180327 (24.64)	88686 (28.52)	51870 (29.68)
Current	129647 (22.65)	166485 (23.61)	168835 (23.07)	65455 (21.05)	32463 (18.58)
Drinking						< 0.0001
None	381736 (66.7)	402174 (57.03)	398383 (54.44)	161354 (51.89)	96115 (55)
Moderate	136879 (23.92)	240927 (34.16)	266239 (36.38)	121719 (39.14)	62158 (35.57)
Heavy2	53675 (9.38)	62114 (8.81)	67176 (9.18)	27900 (8.97)	16482 (9.43)
Regular exercise	0 (0)	9754 (1.38)	89956 (12.29)	267037 (85.87)	174755 (100)	< 0.0001
Hypertension	351028 (61.34)	399757 (56.69)	417175 (57.01)	174445 (56.1)	102436 (58.62)	< 0.0001
Dyslipidemia	331813 (57.98)	406736 (57.68)	415042 (56.72)	175765 (56.52)	98700 (56.48)	< 0.0001
CKD3	68870 (12.03)	65189 (9.24)	64770 (8.85)	24924 (8.01)	16057 (9.19)	< 0.0001
Proteinuria	42377 (7.4)	49028 (6.95)	48986 (6.69)	19388 (6.23)	10904 (6.24)	< 0.0001
SBP (mmHg)	128.75 ± 15.51	128.22 ± 14.97	128.48 ± 14.9	128.27 ± 14.65	128.65 ± 14.84	< 0.0001
DBP (mmHg)	77.96 ± 10.04	78.26 ± 9.98	78.14 ± 9.95	78 ± 9.79	77.59 ± 9.79	< 0.0001
DM medication	416149 (72.72)	492161 (69.79)	515255 (70.41)	219636 (70.63)	129599 (74.16)	< 0.0001
OHA ≥ 3	141666 (24.75)	166098 (23.55)	168821 (23.07)	69974 (22.5)	40569 (23.21)	< 0.0001
Metformin	376811 (65.84)	450165 (63.83)	469403 (64.14)	199852 (64.27)	116508 (66.67)	< 0.0001
SGLT-2 inhibitor	15152 (2.65)	19962 (2.83)	19079 (2.61)	8073 (2.6)	4136 (2.37)	< 0.0001
BMI (kg/m2)	25.38 ± 3.69	25.48 ± 3.6	25.3 ± 3.5	25.2 ± 3.37	24.95 ± 3.22	< 0.0001
WC (cm)	86.45 ± 9.27	86.44 ± 9.1	86.1 ± 8.88	85.66 ± 8.67	85.27 ± 8.47	< 0.0001
DM duration						< 0.0001
New onset	156141 (27.28)	213054 (30.21)	216543 (29.59)	91337 (29.37)	45156 (25.84)
< 5 years	158290 (27.66)	195372 (27.7)	196962 (26.91)	82296 (26.46)	44117 (25.25)
5-9 years	114441 (20)	136083 (19.3)	142641 (19.49)	61138 (19.66)	35642 (20.4)
≥ 10 years	143418 (25.06)	160706 (22.79)	175652 (24)	76202 (24.5)	49840 (28.52)
FBS (mg/dL)	145.15 ± 48.36	146.16 ± 46.64	144.32 ± 44.93	142.82 ± 42.52	140.41 ± 41.09	< 0.0001
TC (mg/dL)	185.61 ± 44.33	186.75 ± 44.17	185.21 ± 43.47	183.88 ± 42.77	180.93 ± 41.95	< 0.0001
HDL-C (mg/dL)	50.5 ± 14.73	50.51 ± 14.5	51.18 ± 14.7	51.68 ± 14.82	52.15 ± 15.26	< 0.0001
LDL-C (mg/dL)	103.35 ± 39.06	104.16 ± 38.79	102.98 ± 38.17	102.25 ± 37.6	100.49 ± 36.83	< 0.0001
eGFR	87.82 ± 49.04	89.88 ± 54.14	90.05 ± 53.23	90.35 ± 55.92	89.03 ± 54.37	< 0.0001
TG (mg/dL)4	140.72 (140.52-140.93)	142.5 (142.31-142.69)	137.04 (136.86-137.22)	131.75 (131.49-132.02)	123.62 (123.29-123.95)	< 0.0001

¹Low income 25%.

²Alcohol consumptions ≥ 30 g/day.

³Estimated glomerular filtration rate < 60 mL/min/1.73 m² using MDRD formula.

⁴Geometric mean (95% confidential interval).

CKD: Chronic kidney disease; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; DM: Diabetes mellitus; OHA: Oral hypoglycemic agents; SGLT: Sodium-glucose cotransporter; BMI: Body mass index; WC: Waist circumference; FBS: Fasting blood glucose; TC: Total cholesterol; HDL: High density lipoprotein; LDL: Low density lipoprotein; TG: Triglyceride; eGFR: Estimated glomerular filtration rate; MET: Metabolic equivalents of tasks.

Table 4 Multivariate cox analysis for incident end-stage renal disease according to diabetes mellitus duration

DM duration	Total (n)	ESRD (n)	Duration PY	IR 1000 PY	Adjusted HR (95% confidence interval)
					Model 1	Model 2	Model 3	Model 4
New onset	722231	1909	4155941	0.46	1 (Reference)	1 (Reference)	1 (Reference)	1 (Reference)
< 5 years	677037	2604	3946270	0.66	1.430 (1.348­1.517)	1.442 (1.359­1.530)	1.179 (1.110­1.252)	1.162 (1.094­1.234)
5-9 years	489945	3978	2829657	1.41	3.050 (2.888­3.221)	2.989 (2.827­3.159)	1.941 (1.832­2.056)	1.790 (1.690­1.896)
≥ 10 years	605818	14868	3389455	4.39	9.558 (9.114­10.025)	9.135 (8.692­9.600)	3.334 (3.158­3.520)	2.624 (2.486­2.770)

Model 1 is non-adjusted; Model 2 is adjusted for age and sex; Model 3 is adjusted model 2 plus income, smoking, drinking, regular exercise, hypertension, dyslipidemia, fasting glucose, oral hyperglycemic agent more than 3, estimated glomerular filtration rate; model 4 is adjusted for model 3 plus proteinuria. DM: Diabetes mellitus; ESRD: End-stage renal disease, PY: Person years; IR: Incidence rate; HR: Hazard ratio.

Table 5 Multivariate cox analysis for incident end-stage renal disease according to exercise intensity

METs-min/week	Total (n)	ESRD (n)	Duration, PY	IR, 1000 PY	Adjusted HR (95% confidence interval)
					Model 1	Model 2	Model 3	Model 4
0	572290	6431	3234371	1.99	1 (Reference)	1 (Reference)	1 (Reference)	1 (Reference)
1-499	705215	6497	4056207	1.60	0.805 (0.778­0.833)	0.856 (0.827­0.886)	0.938 (0.906­0.971)	0.946 (0.913­0.979)
500-999	731798	6501	4215771	1.54	0.775 (0.749­ 0.802)	0.791 (0.764­0.819)	0.917 (0.886­ 0.950)	0.919 (0.888­0.952)
1000-1499	310973	2422	1804581	1.34	0.674 (0.643­ 0.706)	0.683 (0.652­0.716)	0.831 (0.793­0.871)	0.845 (0.806, 0.886)
≥ 1500	174755	1508	1010392	1.49	0.749 (0.709­0.793)	0.697 (0.658­0.737)	0.806 (0.762­0.853)	0.837 (0.791­0.886)

Model 1 is non-adjusted; Model 2 is adjusted for age and sex; Model 3 is adjusted model 2 plus income, smoking, drinking, regular exercise, hypertension, dyslipidemia, fasting glucose, oral hyperglycemic agent more than 3, estimated glomerular filtration rate; model 4 is adjusted for model 3 plus proteinuria. DM: Diabetes mellitus; ESRD: End-stage renal disease, PY: Person years; IR: Incidence rate; HR: Hazard ratio; MET: Metabolic equivalents of tasks.

Table 6 Multivariate cox analysis for incident end-stage renal disease according to exercise intensity

DM duration	METs-min/week	Total (n)	ESRD (n)	Duration, PY	IR, 1000 PY	Adjusted HR (95% Confidence interval)
						Composite		Subgroup
						Model 1	Model 2	Model 1	Model 2
New onset	0	156141	473	888675	0.53	1 (Reference)	1 (Reference)	1 (Reference)	1 (Reference)
	1-499	213054	613	1227517	0.50	0.938 (0.832­1.058)	1.031 (0.914­1.162)	0.938 (0.832­1.058)	1.031 (0.914­1.162)
	500-999	216543	509	1249361	0.41	0.765 (0.675­0.867)	0.864 (0.762­0.980)	0.765 (0.675­0.867)	0.864 (0.762­0.980)
	1000-1499	91337	195	529164	0.37	0.692 (0.585­0.817)	0.753 (0.637­0.890)	0.692 (0.585­0.817)	0.753 (0.637­0.890)
	≥ 1500	45156	119	261225	0.46	0.855 (0.699­1.045)	0.890 (0.728­1.088)	0.855 (0.699­1.045)	0.890 (0.727­1.088)
< 5 years	0	158290	731	914709	0.80	1.495 (1.332­1.678)	1.203 (1.071­1.351)	1 (Reference)	1 (Reference)
	1-499	195372	720	1139960	0.63	1.181 (1.052­1.327)	1.063 (0.946­1.195)	0.790 (0.713­0.876)	0.884 (0.798­0.980)
	500-999	196962	750	1149962	0.65	1.220 (1.087­1.368)	1.082 (0.964­1.214)	0.816 (0.737­0.903)	0.899 (0.812­0.996)
	1000-1499	82296	258	483431	0.53	0.997 (0.857­1.161)	0.949 (0.815­1.104)	0.667 (0.579­0.769)	0.789 (0.684­0.909)
	≥ 1500	44117	145	258209	0.56	1.050 (0.871­1.264)	0.967 (0.803­1.165)	0.702 (0.588­0.839)	0.804 (0.673­0.961)
5-9 years	0	114441	1090	651145	1.67	3.137 (2.816­3.494)	1.771 (1.588­1.976)	1 (Reference)	1 (Reference)
	1-499	136083	1110	787142	1.41	2.640 (2.371­2.940)	1.690 (1.516­1.884)	0.842 (0.774­0.915)	0.954 (0.878­1.038)
	500-999	142641	1139	826498	1.38	2.579 (2.317­2.871)	1.697 (1.523­1.891)	0.822 (0.757­0.894)	0.958 (0.882­1.041)
	1000-1499	61138	402	357285	1.13	2.104 (1.842­2.403)	1.508 (1.319­1.724)	0.671 (0.598­0.752)	0.852 (0.759­0.955)
	≥ 1500	35642	237	207588	1.14	2.135 (1.827­2.496)	1.461 (1.249­1.709)	0.681 (0.592­0.783)	0.825 (0.717­0.949)
≥ 10 years	0	143418	4137	779842	5.30	9.998 (9.091­10.996)	2.635 (2.388­2.908)	1 (Reference)	1 (Reference)
	1-499	160706	4054	901589	4.50	8.454 (7.686­9.298)	2.484 (2.252­2.741)	0.846 (0.810­0.883)	0.943 (0.903­0.985)
	500-999	175652	4103	989951	4.14	7.788 (7.081­8.565)	2.423 (2.197­2.672)	0.779 (0.746­0.813)	0.919 (0.880­0.960)
	1000-1499	76202	1567	434702	3.60	6.764 (6.103­7.497)	2.284 (2.056­2.538)	0.677 (0.638­0.717)	0.867 (0.818­0.919)
	≥ 1500	49840	1007	283371	3.55	6.671 (5.980­7.441)	2.213 (1.979­2.475)	0.667 (0.623­0.715)	0.840 (0.784­0.900)

Model 1 is non-adjusted; model 2 is adjusted for age and sex, income, smoking, drinking, regular exercise, hypertension, dyslipidemia, fasting glucose, oral hyperglycemic agent more than 3, estimated glomerular filtration rate, protein. DM: Diabetes mellitus; ESRD: End-stage renal disease, PY: Person years; IR: Incidence rate; HR: Hazard ratio; MET: Metabolic equivalents of tasks.