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Sune Moeller Skov-Jeppesen,1,2 Nicky Anúel Petersen,1 Knud Bonnet Yderstraede,2,3 Boye L Jensen,4 Claus Bistrup,2,5 Lars Lund1,2 1Department of Urology, Odense University Hospital, Odense, Denmark; 2Clinical Institute, University of Southern Denmark, Odense, Denmark; 3Department of Endocrinology, Odense University Hospital, Odense, Denmark; 4Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; 5Department of Nephrology, Odense University Hospital, Odense, DenmarkCorrespondence: Sune Moeller Skov-Jeppesen, Department of Urology, Odense University Hospital, Sdr. Boulevard 29, Odense, 5000, Denmark, Tel +45 51210911, Fax +45 65411726, Email sun_mjep@hotmail.comBackground: 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.Keywords: review, kidney disease, extracorporeal shockwave therapy, ESWT

Sune Moeller Skov-Jeppesen,1– 3 Knud Bonnet Yderstraede,3,4 Boye L Jensen,5 Claus Bistrup,3,6 Milad Hanna,7 Lars Lund1,3 1Department of Urology, Odense University Hospital, Odense, Denmark; 2OPEN, Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark; 3Clinical Institute, University of Southern Denmark, Odense, Denmark; 4Department of Endocrinology, Odense University Hospital, Odense, Denmark; 5Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; 6Department of Nephrology, Odense University Hospital, Odense, Denmark; 7Department of Urology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UKCorrespondence: Sune Moeller Skov-JeppesenDepartment of Urology, Odense University Hospital, Sdr. Boulevard 29, Odense C, 5000, DenmarkTel +45 51210911Fax +45 65411726Email sun_mjep@hotmail.comPurpose: Treatment with low-intensity shockwave therapy (LI-ESWT) is associated with angiogenesis and is suggested as a treatment for different types of vascular diseases. It was hypothesized that LI-ESWT improves the renal filtration barrier and halts the progression of GFR decline in diabetic kidney disease (DKD) potentially through VEGF and NO formation. We present the first data on LI-ESWT in human DKD.Methods: The study was designed as an interventional, prospective, one-arm, Phase 1 study. We investigated change in GFR and albuminuria in 28 patients with DKD treated with six sessions of LI-ESWT over three weeks. The patients were followed for six months. Urine excretion of kidney injury markers, vascular endothelial growth factor (VEGF) and nitric oxide metabolites (NOx) was studied after LI-ESWT.Results: There were no significant changes in GFR and albuminuria up to six months after LI-ESWT compared to baseline. Urine VEGF was transiently reduced one month after LI-ESWT, but there were no other significant changes in urine VEGF or NOx after LI-ESWT. Secondary analysis showed that NOx increased after LI-ESWT in patients who had low levels of NOx at baseline. Kidney injury marker trefoil factor 3 (TFF3) increased acutely after the first session of LI-ESWT indicating transient endothelial repair. Other markers of kidney injury were stable in relation to LI-ESWT.Conclusion: LI-ESWT treatment did not significantly improve kidney function and albumin excretion. It is concluded that LI-ESWT is not harmful. A randomized blinded study should be performed to clarify whether adjunctive treatment with LI-ESWT is superior to standard treatment of DKD.Keywords: albuminuria, clinical trial, diabetic kidney disease, glomerular filtration rate, ESWT, extracorporeal shockwave therapy