Low-Intensity Shockwave Therapy (LI-ESWT) in Diabetic Kidney Disease: Results from an Open-Label Interventional Clinical Trial

Figures & data

Figure 1 Overview of investigations.

Box 1 Inclusion and Exclusion Criteria

Inclusion

Patients with DM and stage 3 CKD

Exclusion

Non-DM kidney disease^a

Kidney or ureteral stone

Obstructive uropathy

Untreated urinary tract infection

Kidney tumor^b

Anticoagulant medical therapy^c

Bleeding disorder

Pregnancy

Office blood pressure >140/90 mmHg

Abnormal renogramme^d

Single kidney

Kidney transplant

AMI within one year

Severe psychiatric disease

Notes: ^aPatients where non-DM kidney disease was suspected from medical history or clinical evaluation. ^bPatients with simple renal cortical cysts (Bosniak class I and II) were allowed to participate. ^cPatients receiving platelet inhibitors were allowed to participate. ^d<30% function on one kidney

Table 1 Baseline Demographics

Sex
Male	20 (71%)
Female	8 (29%)
Age (years)	61 (54; 69)
Body mass index (kg/m2)	28 (22; 32)
Smoking
Current	3 (11%)
Former	15 (54%)
Never	10 (36%)
Package years, none-smokers excluded	18 (7; 41)
Alcohol consumption (12g/week)	1 (0; 5)
Diabetes mellitus
Type 1	6 (21%)
Type 2	19 (68%)
Other (MODY/LADA)	3 (11%)
Duration of diabetes (years)	25 (13; 35)
Medical treatment of diabetes mellitus
None	1 (4%)
Metformin	7 (25%)
Insulin	23 (82%)
Sulfunylurea	2 (7%)
DPP-4 inh./GLP-1-RA/SGLT2-inh.	7 (25%)
Medical treatment of hypertension
None	3 (11%)
ACE-inhibitor /AT2-antagonist	23 (82%)
Thiazide	14 (50%)
Furosemide	12 (43%)
Beta-blocker	8 (29%)
Calcium-antagonist	15 (54%)
Other	9 (32%)
Receiving lipid-lowering medication	25 (89%)
Charlson Index score^a
2	12 (43%)
3–4	13 (46%)
5 or more	3 (11%)

Notes: Data are number (%) or median (25% quartile ; 75% quartile). ^aMinimum Charlson Index Score is 2 according to the diagnosis of diabetic nephropathy in all patients.

Table 2 Outcome Variables

		Baseline	1 Month	3 Months	6 Months	p-value^a
51-chromium-EDTA clearance
Standard-GFR	mL/min/1.73m2	37.0 (27.3; 49.0)	-	36.0 (27.0; 46.8)	37.0 (24.0; 51.0)	0.351
Albuminuria^b
Albumin (total)	mg/24hours	302 (78; 786)	253 (80; 1167)	295 (58; 907)	214 (100; 987)	0.801
24-hour urine
Volume	Ml	2332 (1822; 2541)	2437 (1626; 2703)	2318 (1647; 2838)	2180 (1678; 2763)	0.532
Creatinine clearance	mL/min	56.2 (36.5; 70.1)	51.8 (35.8; 74.9)	58.0 (38.9; 73.3)	58.4 (28.5; 73.4)	0.165
Sodium	mmol/24hours	189 (141; 214)	199 (148; 224)	170 (123; 243)	170 (115; 216)	0.341
Potassium	mmol/24hours	65 (49; 82)	65 (54; 90)	70 (48; 92)	65 (52; 87)	0.307
Ambulatory blood pressure
Systolic	mmHg	126 (119; 133)	124 (119; 138)	126 (119; 134)	123 (117; 137)	0.534
Diastolic	mmHg	70 (64; 79)	72 (63; 77)	71 (65; 79)	69 (65; 78)	0.918
Blood samples
Hemoglobin	mmol/L	8.2 (7.3; 8.7)	8.0 (7.3; 8.4)	8.2 (7.3; 8.5)	8.0 (7.5; 8.4)	0.967
Albumin	g/L	43 (41; 45)	43 (40; 45)	42 (40; 44)	42 (41; 44)	0.228
Sodium	mmol/L	138 (135; 141)	139 (136; 141)	137 (136; 140)	139 (137; 141)	0.081
Potassium	mmol/L	4.2 (3.9; 4.5)	4.5 (4.1; 4.6)	4.3 (4.1; 4.6)	4.4 (4.0; 4.7)	0.736
Ionised calcium	mmol/L	1.26 (1.20; 1.29)	1.25 (1.21; 1.27)	1.24 (1.21; 1.27)	1.25 (1.22; 1.29)	0.493
Phosphate	mmol/L	1.05 (0.93; 1.16)	1.08 (0.97; 1.20)	1.07 (0.93; 1.17)	1.07 (0.95; 1.17)	0.992
Creatinine	µmol/L	149 (128; 189)	154 (121; 201)	159 (121; 200)	168 (118; 199)	0.271
eGFR	mL/min/1.73m2	38 (31; 48)	39 (28; 48)	37 (28; 46)	34 (25; 47)	0.473
BUN	mmol/L	10.4 (8.8; 14.3)	11.8 (9.1; 14.3)	11.9 (8.6; 13.2)	13.7 (8.6; 15.8)	0.038^c
Glycated hemoglobin	mmol/mol	61 (53; 75)	60 (55; 75)	61 (54; 71)	64 (55; 69)	0.756

Notes: Data are presented as median (25% quartile; 75% quartile). ^aFriedman test. ^bPatients with non-significant albuminuria are excluded (6 patients with <30 mg/24-hour at all visits). ^cUnadjusted post-hoc test showed significant difference between baseline BUN and 6 months BUN (p=0.018) and between 3 months BUN and 6 months BUN (p=0.031). Post-hoc test adjusted for multiple testing (Bonferroni method) showed no significant pair-wise differences between the visits.

Table 3 Molecular Markers

		Baseline	1. Treatment	6. Treatment	1 Month	3 Months	6 Months
NOx	µg/mmol	8.9 (5.3; 19.2)	12.6 (7.5; 20.2)	10.6 (8.0; 18.8)	11.7 (7.1; 22.8)	13.1 (5.4; 17.7)	10.5 (5.4; 23.2)
VEGF	ng/mmol	76.0 (36.3; 123.1)	66.6 (32.8; 99.4)	72.2 (45.8; 138.8)	54.9 (39.5; 101.7)^a	56.8 (32.9; 120.0)	56.0 (34.8; 140.3)
KIM-1	ng/mmol	394 (62.2; 1150)	69.8 (47.0; 120.7)	375 (78.7; 1257)	431 (57.7; 1346)	549 (69.3; 1336)	190 (76.2; 1004)
Calbindin	ng/mmol	367 (286; 760	412 (230; 726)	361 (297; 664)	357 (275; 595)	388 (228; 613)	351 (242; 490)
Clusterin	ng/mmol	8137 (3131; 23,486)	4699 (2780; 17,732)	7630 (3513; 32,508)	6858 (2936; 18,462)	6706 (3491; 26,896)	5155 (2798; 16,876)
Osteoactivin	ng/mmol	407 (225; 1094)	750 (434; 1273)	404 (279; 972)	351 (215; 895)	370 (159; 550)	451 (212; 1128)
TFF3	ng/mmol	13.3 (8.6; 33.7)	23.1 (12.2; 66.5)^b	13.2 (6.9; 34.2)	9.9 (5.3; 32.6)	7.3 (2.0; 40.2)	12.7 (5.3; 26.0)

Notes: Data are shown as median (IQR). The concentrations of the markers were normalized to creatinine concentration (mmol/l). All follow-up values were compared to baseline using related-samples Wilcoxon signed rank test. Significance level was set at p<0.10. Significant results are tagged and highlighted in bold. ^ap=0.056. ^bp=0.030.

Figure 2 Individual curves representing albuminuria (A) and GFR (B) in each patient during the study.

Figure 3 Individual curves representing VEGF (A), NOx (B) and TFF3 (C) in each patient during the study.