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Skov-Jeppesen SM. et al., 2023: Low-Intensity Extracorporeal Shockwave Therapy (LI-ESWT) in Renal Diseases: A Review of Animal and Human Studies

Skov-Jeppesen SM, Petersen NA, Yderstraede KB, Jensen BL, Bistrup C, Lund L.
Department of Urology, Odense University Hospital, Odense, Denmark.
Clinical Institute, University of Southern Denmark, Odense, Denmark.
Department of Endocrinology, Odense University Hospital, Odense, Denmark.
Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Department of Nephrology, Odense University Hospital, Odense, Denmark.

Abstract

Background: Low-intensity extracorporeal shockwave therapy (LI-ESWT) has been suggested as a treatment for vascular diseases such as ischemic heart disease, diabetic foot ulcers, and erectile dysfunction. Primarily, LI-ESWT is known for its ability to stimulate angiogenesis and activation of stem cells in target tissues. Application of LI-ESWT in chronic progressive renal diseases is a novel area. The aim of the present review was to summarize available data on the effects of LI-ESWT used in the setting of renal diseases.

Methods: We systematically searched PubMed, Medline, and Embase databases for relevant studies. Our review included the results from preclinical animal experiments and clinical research.

Results: Eleven animal studies and one clinical study were included in the review. In the animal studies, LI-ESWT was used for the treatment of hypertensive nephropathy (n=1), diabetic nephropathy (n=1), or various types of ischemic renal injury (ie, artery occlusion, reperfusion injury) (n=9). The clinical study was conducted in a single-arm cohort as a Phase 1 study with patients having diabetic nephropathy. In animal studies, the application of LI-ESWT was associated with several effects: LI-ESWT led to increased VEGF and endothelial cell proliferation and improved vascularity and perfusion of the kidney tissue. LI-ESWT reduced renal inflammation and fibrosis. LI-ESWT caused only mild side effects in the clinical study, and, similarly, there were no signs of kidney injury after LI-ESWT in the animal studies.

Conclusion: LI-ESWT, as a non-invasive treatment, reduces the pathological manifestations (inflammation, capillary rarefaction, fibrosis, decreased perfusion) associated with certain types of renal disease. The efficacy of renal LI-ESWT needs to be confirmed in randomized clinical trials.
Int J Nephrol Renovasc Dis. 2023 Feb 6;16:31-42. doi: 10.2147/IJNRD.S389219. eCollection 2023. PMID: 36778197. FREE ARTICLE

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Comments 1

Jens Rassweiler on Wednesday, 14 June 2023 10:30

Low-intensity extracorporeal shockwave therapy (LI-ESWT) has been suggested as a treatment for vascular diseases such as ischemic heart disease, diabetic foot ulcers, and erectile dysfunction. Primarily, LI-ESWT is known for its ability to stimulate angiogenesis and activation of stem cells in target tissues.

Chronic kidney disease (CKD) is characterized by irreversible pathological lesions of the kidney tissue including vascular rarefaction, interstitial fibrosis, and tubular atrophy. In particular, diabetic nephropathy and hypertensive nephropathy are major culprits leading to end-stage kidney disease that is associated with microvascular degeneration and glomerulosclerosis. Other causes that might promote CKD include acute transient renal ischemia, toxic insults/effects, and autoimmune disorders. LI-ESWT could prove as a feasible method to ameliorate the chronic manifestations of renal diseases and preserve kidney function.

Application of LI-ESWT in chronic progressive renal diseases is a novel area. The aim of the present systematic review was to summarize available data on the effects of LI-ESWT used in the setting of renal diseases. LI-ESWT was defined as shockwave therapy carried out with focal zone energy flux below 0.35 mJ/mm2 (low to medium energy level) in accordance with the guidelines provided by the International Society for Medical Shockwave Treatment (ISMST). The authors identified a total of 12 eligible studies. Of these, 11 were animal studies and one was a clinical study.2 preclinical animal studies and 2 clinical studies were non-eligible since they were only published in abstract format.

Animal studies: Six of the animal studies used rats, and five studies used pigs. In the animal studies, different types of renal disease were induced by either Nω-nitro-L-arginine methyl ester (L-NAME) ingestion (hypertension, n=1), streptozotocin injection (type 1 diabetes mellitus, n=1), or renal artery occlusion/stenosis (hypoxic ischemia, n=9).
The number of LI-ESWT treatment sessions varied from one single treatment up to a maximum of 12 treatments. The most common protocol for LI-ESWT treatment was two sessions per week for 3 weeks (n=5). LI-ESWT was applied either unilaterally (n=9) or bilaterally (n=2). In the studies with rats, the dosage of LI-ESWT per session varied from 180 shocks/kidneyup to 400 shocks/kidney. In the five porcine studies, the dosage of LI-ESWT was the same: the stenotic kidney was divided into small zones and each zone was treated with 200 shocks, ie, 4800– 5200 shocks/session. The lowest energy level was 0.09 mJ/mm2 and the highest energy level that was used was 0.13 mJ/mm2. LI-ESWT was carried out using Storz Duolith SD1 (n=2), Medispec Omnispec Vetspec (n=5), Wikkon.HK. ESWL-Vm (n=1), a special Medispec device (n=1), High Medical Technologies EvoTron R05, or EMS DolorClast.

Clinical studies: Skov-Jeppesen et al (main author) published a safety report from a clinical study that included measurement of renal functional outcomes after LI-ESWT in patients with diabetic nephropathy. Other studies have reported data only in abstract format. The study by Skov-Jeppesen et al was a single-arm cohort study including 28 patients. In this study, LI-ESWT was applied with a Storz Modulith SLX-2 device and both kidneys were treated on upper, middle, and lower zone with 1000 shocks/zone and energy 0.265 mJ/mm2.
Concerning molecular effects, available data do not show consistent changes in VEGF and NO-synthase in kidney tissue subjected to LI-ESWT. A chemoattractant for endothelial progenitor cells, was higher after LI-ESWT in the setting of renal ischemia, diabetic nephropathy, and proteinuric CKD16 but not in hypertensive renal disease. Furthermore, LI-ESWT seemed to downregulate TGF-beta expression in the studies by Zhang et al 2016, Sung et al,1 and Hsiao et al This could indicate that LI-ESWT counteracts the initiation of fibrosis. Concerning histological observations, a common finding was lower interstitial fibrosis after LI-ESWT as demonstrated by trichrome staining at 4 weeks, 7 weeks, and 60 days. Nonetheless, two studies found no effect of LI-ESWT on the degree of renal fibrosis at 4 days (which is not surprising) and 4 weeks after the treatment. LI-ESWT promoted endothelial cell proliferation and increased renal vascularity. On microCT scan, the density of small renal vessels recovered after LI-ESWT. Three studies found higher number of peritubular capillaries after LI-ESWT. Other studies reported ameliorated vascular and glomerular lesions after LI-ESWT1 as well as lymphangiogenesis. In diabetic rats, LI-ESWT promoted regeneration of glomerular podocyte cells. In summary, available data show stimulatory effects of LI-ESWT on kidney microvessel density and growth.

Four studies demonstrated that single kidney GFR was significantly higher in pigs 4 weeks after LI-ESWT administration as evidenced by multidetector computed tomography (MDCT). In the clinical study, GFR was measured in patients by means of chrome-EDTA clearance. After six sessions of LI-ESWT, GFR was stable in patients with diabetic nephropathy up to 6 months. In five of the animal studies, LI-ESWT lowered the plasma concentration of creatinine, BUN, or cystatin C, but there was no significant effect on these parameters in the studies by Caron et al and Chen et al. Importantly, LI-ESWT ameliorated albuminuria and proteinuria in preclinical settings. In rats, proteinuria was lower 60 days after LI-ESWT in proteinuric CKD, and albuminuria was lower than 6 weeks after LI-ESWT in diabetic nephropathy. In pigs with renal ischemia, Zhao et al demonstrated that the urinary protein excretion was lowered at 4 weeks after LI-ESWT. However, the studies by Caron et al and Zhang et al did not corroborate this. In human diabetic nephropathy, there were no significant changes in median albuminuria 6 months after LI-ESWT. In summary, LI-ESWT is neutral or slightly beneficial on GFR and albuminuria, but material is scarce and follow-up time is limited.
Concerning safety of LI-ESWT, it was applied to a healthy control group in four of the animal studies allowing the study of side effects to the treatment. In rat studies, no histological changes were seen after application of LI-ESWT to healthy animals: LI-ESWT did not adversely affect urinary protein excretion, arterial blood pressure, or renal function. In the published study with data from patients with diabetes, there was transient macroscopic haematuria in six out of 28 patients after LI-ESWT. Treatment with LI-ESWT caused short-lasting flank tenderness in the majority of the patients, and ultrasound scanning revealed no signs of renal hematoma. There were no correlations between the presence of haematuria and negative functional outcomes in the patients. During the intervention, the patients experienced LI-ESWT as a stinging sensation, but pain was only reported in 1/14 patients. Importantly, in patients with diabetic nephropathy, LI-ESWT had no negative impact on urinary kidney injury markers (KIM-1, calbindin, clusterin, osteoactivin, trefoil factor-3).
In conclusion, LI-ESWT, as a non-invasive treatment, reduces the pathological manifestations (inflammation, capillary rarefaction, fibrosis, decreased perfusion) associated with certain types of renal disease. The efficacy of renal LI-ESWT needs to be confirmed in randomized clinical trials.
Variation of the results can be ascribed to different models of renal disease, different species, and different therapeutic protocols. In light of the non-invasive intervention, there is a need for functional and tissue data from human intervention trials. The beneficial downstream signaling effects of LI-ESWT involve local angiogenesis as well as anti-inflammatory processes summarizing into reduced fibrosis. At the level of signaling pathways, LI-ESWT upregulates VEGF and NO which act as trophic factors for endothelium and stimulation of angiogenesis. VEGF and VEGF receptor activation were previously shown to be higher after LI-ESWT in heart, skeletal muscle, skin, and penile tissue.
Only a few studies have tested the dose–response relationship of LI-ESWT. The treatment can be administered with lower or higher energy within the spectrum from 0.01 to 0.35 mJ/mm2. In the hind limb of rats, tissue oxygen tension was significantly higher after application with energy at 0.30 mJ/mm2 compared to energy at 0.10 mJ/mm2. n renal diseases, LI-ESWT was carried out as focused therapy in all of the studies and the potential of radial LI-ESWT is unknown.
In general, LI-ESWT was applied with energy densities in the lower end of the spectrum in the animal studies (0.09–0.13 mJ/mm2). Conversely, patients included in the clinical study were treated with relatively high energy levels at 0.265 mJ/mm2. There were no clear associations between the frequency or number of sessions of LI-ESWT and the outcomes. The most frequently used protocol for LI-ESWT was twice per week for 3 weeks for a total of six sessions but ranged from one session up to 12 sessions in total. A consistent finding across the preclinical studies was that there was no evidence of injury or damage to the kidneys.
The clinical study demonstrated. transient macroscopic haematuria in a minor part of the patients. Flank tenderness was more commonly reported after bilateral LI-ESWT. These side effects are well-known also from ESWL. The side effects did not require any intervention or treatment and were short-lasting after LI-ESWT. There were no reported signs of renal hematoma or negative functional outcomes (drop in GFR, hypertension, or albuminuria) related to LI-ESWT, and further clinical research is encouraged. In particular, future clinical studies should test the dose– response relationship of LI-ESWT considering the positive results demonstrated in animal studies at relatively low energy settings.
Obviously, the effect of Li-ESWT on renal function is a very complex issue, because of the versatility of the underlying causes. I would strongly recommend to focus on the application of lower energy settings in future studies. Flank pain and hematuria after the treatment indicate an overdosage. It has to be taken into consideration, that the effect of LI-ESWT may not only depend on the given energy density, but also on the focal size, which is much bigger in case of the Modulith SLX-F2 compared to the hand-held devices.

Jens Rassweiler

Low-intensity extracorporeal shockwave therapy (LI-ESWT) has been suggested as a treatment for vascular diseases such as ischemic heart disease, diabetic foot ulcers, and erectile dysfunction. Primarily, LI-ESWT is known for its ability to stimulate angiogenesis and activation of stem cells in target tissues. Chronic kidney disease (CKD) is characterized by irreversible pathological lesions of the kidney tissue including vascular rarefaction, interstitial fibrosis, and tubular atrophy. In particular, diabetic nephropathy and hypertensive nephropathy are major culprits leading to end-stage kidney disease that is associated with microvascular degeneration and glomerulosclerosis. Other causes that might promote CKD include acute transient renal ischemia, toxic insults/effects, and autoimmune disorders. LI-ESWT could prove as a feasible method to ameliorate the chronic manifestations of renal diseases and preserve kidney function. Application of LI-ESWT in chronic progressive renal diseases is a novel area. The aim of the present systematic review was to summarize available data on the effects of LI-ESWT used in the setting of renal diseases. LI-ESWT was defined as shockwave therapy carried out with focal zone energy flux below 0.35 mJ/mm2 (low to medium energy level) in accordance with the guidelines provided by the International Society for Medical Shockwave Treatment (ISMST). The authors identified a total of 12 eligible studies. Of these, 11 were animal studies and one was a clinical study.2 preclinical animal studies and 2 clinical studies were non-eligible since they were only published in abstract format. Animal studies: Six of the animal studies used rats, and five studies used pigs. In the animal studies, different types of renal disease were induced by either Nω-nitro-L-arginine methyl ester (L-NAME) ingestion (hypertension, n=1), streptozotocin injection (type 1 diabetes mellitus, n=1), or renal artery occlusion/stenosis (hypoxic ischemia, n=9). The number of LI-ESWT treatment sessions varied from one single treatment up to a maximum of 12 treatments. The most common protocol for LI-ESWT treatment was two sessions per week for 3 weeks (n=5). LI-ESWT was applied either unilaterally (n=9) or bilaterally (n=2). In the studies with rats, the dosage of LI-ESWT per session varied from 180 shocks/kidneyup to 400 shocks/kidney. In the five porcine studies, the dosage of LI-ESWT was the same: the stenotic kidney was divided into small zones and each zone was treated with 200 shocks, ie, 4800– 5200 shocks/session. The lowest energy level was 0.09 mJ/mm2 and the highest energy level that was used was 0.13 mJ/mm2. LI-ESWT was carried out using Storz Duolith SD1 (n=2), Medispec Omnispec Vetspec (n=5), Wikkon.HK. ESWL-Vm (n=1), a special Medispec device (n=1), High Medical Technologies EvoTron R05, or EMS DolorClast. Clinical studies: Skov-Jeppesen et al (main author) published a safety report from a clinical study that included measurement of renal functional outcomes after LI-ESWT in patients with diabetic nephropathy. Other studies have reported data only in abstract format. The study by Skov-Jeppesen et al was a single-arm cohort study including 28 patients. In this study, LI-ESWT was applied with a Storz Modulith SLX-2 device and both kidneys were treated on upper, middle, and lower zone with 1000 shocks/zone and energy 0.265 mJ/mm2. Concerning molecular effects, available data do not show consistent changes in VEGF and NO-synthase in kidney tissue subjected to LI-ESWT. A chemoattractant for endothelial progenitor cells, was higher after LI-ESWT in the setting of renal ischemia, diabetic nephropathy, and proteinuric CKD16 but not in hypertensive renal disease. Furthermore, LI-ESWT seemed to downregulate TGF-beta expression in the studies by Zhang et al 2016, Sung et al,1 and Hsiao et al This could indicate that LI-ESWT counteracts the initiation of fibrosis. Concerning histological observations, a common finding was lower interstitial fibrosis after LI-ESWT as demonstrated by trichrome staining at 4 weeks, 7 weeks, and 60 days. Nonetheless, two studies found no effect of LI-ESWT on the degree of renal fibrosis at 4 days (which is not surprising) and 4 weeks after the treatment. LI-ESWT promoted endothelial cell proliferation and increased renal vascularity. On microCT scan, the density of small renal vessels recovered after LI-ESWT. Three studies found higher number of peritubular capillaries after LI-ESWT. Other studies reported ameliorated vascular and glomerular lesions after LI-ESWT1 as well as lymphangiogenesis. In diabetic rats, LI-ESWT promoted regeneration of glomerular podocyte cells. In summary, available data show stimulatory effects of LI-ESWT on kidney microvessel density and growth. Four studies demonstrated that single kidney GFR was significantly higher in pigs 4 weeks after LI-ESWT administration as evidenced by multidetector computed tomography (MDCT). In the clinical study, GFR was measured in patients by means of chrome-EDTA clearance. After six sessions of LI-ESWT, GFR was stable in patients with diabetic nephropathy up to 6 months. In five of the animal studies, LI-ESWT lowered the plasma concentration of creatinine, BUN, or cystatin C, but there was no significant effect on these parameters in the studies by Caron et al and Chen et al. Importantly, LI-ESWT ameliorated albuminuria and proteinuria in preclinical settings. In rats, proteinuria was lower 60 days after LI-ESWT in proteinuric CKD, and albuminuria was lower than 6 weeks after LI-ESWT in diabetic nephropathy. In pigs with renal ischemia, Zhao et al demonstrated that the urinary protein excretion was lowered at 4 weeks after LI-ESWT. However, the studies by Caron et al and Zhang et al did not corroborate this. In human diabetic nephropathy, there were no significant changes in median albuminuria 6 months after LI-ESWT. In summary, LI-ESWT is neutral or slightly beneficial on GFR and albuminuria, but material is scarce and follow-up time is limited. Concerning safety of LI-ESWT, it was applied to a healthy control group in four of the animal studies allowing the study of side effects to the treatment. In rat studies, no histological changes were seen after application of LI-ESWT to healthy animals: LI-ESWT did not adversely affect urinary protein excretion, arterial blood pressure, or renal function. In the published study with data from patients with diabetes, there was transient macroscopic haematuria in six out of 28 patients after LI-ESWT. Treatment with LI-ESWT caused short-lasting flank tenderness in the majority of the patients, and ultrasound scanning revealed no signs of renal hematoma. There were no correlations between the presence of haematuria and negative functional outcomes in the patients. During the intervention, the patients experienced LI-ESWT as a stinging sensation, but pain was only reported in 1/14 patients. Importantly, in patients with diabetic nephropathy, LI-ESWT had no negative impact on urinary kidney injury markers (KIM-1, calbindin, clusterin, osteoactivin, trefoil factor-3). In conclusion, LI-ESWT, as a non-invasive treatment, reduces the pathological manifestations (inflammation, capillary rarefaction, fibrosis, decreased perfusion) associated with certain types of renal disease. The efficacy of renal LI-ESWT needs to be confirmed in randomized clinical trials. Variation of the results can be ascribed to different models of renal disease, different species, and different therapeutic protocols. In light of the non-invasive intervention, there is a need for functional and tissue data from human intervention trials. The beneficial downstream signaling effects of LI-ESWT involve local angiogenesis as well as anti-inflammatory processes summarizing into reduced fibrosis. At the level of signaling pathways, LI-ESWT upregulates VEGF and NO which act as trophic factors for endothelium and stimulation of angiogenesis. VEGF and VEGF receptor activation were previously shown to be higher after LI-ESWT in heart, skeletal muscle, skin, and penile tissue. Only a few studies have tested the dose–response relationship of LI-ESWT. The treatment can be administered with lower or higher energy within the spectrum from 0.01 to 0.35 mJ/mm2. In the hind limb of rats, tissue oxygen tension was significantly higher after application with energy at 0.30 mJ/mm2 compared to energy at 0.10 mJ/mm2. n renal diseases, LI-ESWT was carried out as focused therapy in all of the studies and the potential of radial LI-ESWT is unknown. In general, LI-ESWT was applied with energy densities in the lower end of the spectrum in the animal studies (0.09–0.13 mJ/mm2). Conversely, patients included in the clinical study were treated with relatively high energy levels at 0.265 mJ/mm2. There were no clear associations between the frequency or number of sessions of LI-ESWT and the outcomes. The most frequently used protocol for LI-ESWT was twice per week for 3 weeks for a total of six sessions but ranged from one session up to 12 sessions in total. A consistent finding across the preclinical studies was that there was no evidence of injury or damage to the kidneys. The clinical study demonstrated. transient macroscopic haematuria in a minor part of the patients. Flank tenderness was more commonly reported after bilateral LI-ESWT. These side effects are well-known also from ESWL. The side effects did not require any intervention or treatment and were short-lasting after LI-ESWT. There were no reported signs of renal hematoma or negative functional outcomes (drop in GFR, hypertension, or albuminuria) related to LI-ESWT, and further clinical research is encouraged. In particular, future clinical studies should test the dose– response relationship of LI-ESWT considering the positive results demonstrated in animal studies at relatively low energy settings. Obviously, the effect of Li-ESWT on renal function is a very complex issue, because of the versatility of the underlying causes. I would strongly recommend to focus on the application of lower energy settings in future studies. Flank pain and hematuria after the treatment indicate an overdosage. It has to be taken into consideration, that the effect of LI-ESWT may not only depend on the given energy density, but also on the focal size, which is much bigger in case of the Modulith SLX-F2 compared to the hand-held devices. Jens Rassweiler
Friday, 24 May 2024