Short summary

We aim to investigate whether low energy shockwave therapy (LE-SWT) can preserve kidney function in diabetic patients. Participants in this study will receive LE-SWT treatment 6 times over 3 weeks. The treatment is non-invasive and has no known side effects. Previous studies have shown that LE-SWT induces angiogenesis.

The aim of this study is to demonstrate that Low Energy Shockwave Treatment improves or stabilizes renal function in diabetic patients - thereby potentially reducing patients' morbidity and mortality.

We hypothesize that Low Energy Shockwave Therapy (LE-SWT) performed on diabetic patients' kidneys with the Modulith SLX-F2 lithotripter:

1. Increases glomerular function measured by chrom-EDTA clearance at 3, 6, and 18 months post treatment.
2. Stimulates Nitric Oxide (NO) release measured as increased levels of NO metabolites, nitrate and nitrite, and cyclic Guanosine Monophosphate (cGMP) in patients' spot urine.
3. Does not cause increased urinary levels of markers for tubular and glomerular damage, i.e. Neutrophil Gelatinase-Associated Lipocalin (NGAL) and albumin. 
4. Induces angiogenesis and prevents fibrosis in kidney tissue as shown by kidney biopsy histology and quantitative measures of endothelium using fluorescent marking of CD34 positive cells. Furthermore, LE-SWT protects from destruction of the glomerular basal lamina as revealed on electron microscopy. 
5. Improves self-reported quality of life measured by using the Short Form 36 version 2 (SF-36v2) health survey.
6. Causes no clinical side effects

Rationale

Definition of chronic kidney disease

The Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) defines chronic kidney disease as either kidney damage or a decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73m2 for 3 or more months.

Whatever the underlying etiology, the destruction of renal mass with irreversible sclerosis and loss of nephrons leads to a progressive decline in GFR. The different stages of chronic kidney disease form a continuum in time. In 2002, K/DOQI published its classification of the stages of chronic kidney disease (CKD), as follows:

Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m2)

Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m2)

Stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 m2)

Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m2)

Stage 5: Kidney failure (GFR<15 mL/min/1.73 m2)

Epidemiology

There is a rising incidence and prevalence of kidney failure with poor outcomes and high costs. The Third National Health and Examination Survey (NHANES III) estimated that the prevalence of chronic kidney disease in adults in the United States was 11% (19.2 million). The prevalence of chronic kidney disease stages 1-4 increased from 10% in 1988-1994 to 13.1% in 1999-2004. This increase is partially explained by the increase in the prevalence of diabetes and hypertension, the two most common causes of chronic kidney disease. Data from the United States Renal Data System (USRDS) show that the prevalence of chronic renal failure increased 104% between the years 1990-2001 and incidence rates have risen 30 % between 1992 and 2008.

Diabetic nephropathy is one of the most devastating complications of diabetes. It remains the leading cause of end stage renal disease (ESRD), accounting for 44% of ESRD incident cases in the United States.

Etiology

The single most important factor responsible for the increasing incidence of CKD is diabetes mellitus. Renal affection includes albuminuria, hypertension and a decline in kidney function. Blood pressure control, which is difficult to achieve in diabetics, is mandatory for long term prognosis.

Prognosis

Many patients with chronic kidney disease might progress to ESRD. The rate of the progression depends on the underlying diagnosis, on the successful implementation of secondary preventive measures and on the individual patient.

At every age, patients with ESRD on dialysis have significantly increased morbidity and mortality when compared with non-dialysis patients and individuals without kidney disease. ESRD is the major cause of death accounting for 59-66% in patients with type 1 DM and nephropathy.

The medical care of patients with chronic kidney disease usually focus on the following:

• Delaying or halting the progression of chronic kidney disease
• Treating the pathologic manifestations of chronic kidney disease

However, no treatments are available to reverse the effects of CKD.

Description of the cohort

30 patients with moderate kidney failure will be recruited from the Department of Endocrinology OUH. LEST treatment will be performed in the ambulatory of the Department of Urology. Patients will be hospitalized for 1 day in the Department of Nephrology when kidney biopsy is taken (two times in study period).

Inclusion criteria

• CKD stage 3: Moderate reduction in GFR in patients with DM
• Age 18-65 years

Exclusion criteria

• CKD stage 1, 2, 4, 5.
• Blood pressure above 140/90 mmHg
• Renography with less than 30 % differential function on one kidney
• Kidney or ureteric stone
• Obstructive uropathy
• Kidney tumor
• Chronic Urinary Tract Infection (UTI)
• Single kidney
• Bleeding disorders (coagulopathy)
• Patient on anticoagulantia
• Coronary infarction during study period
• LE-SWT for other reasons and non-DM kidney disease
• Severe psychiatric disorder
• Kidney transplant recipient
• Pregnant or planning on becoming pregnant

Data and biological material

• Chrome-EDTA clearance
• Kidney biopsy
• Ultrasound investigation kidney and urinary tract
• Blood sampling
• Ambulatory blood pressure
• 24 hour urine sampling
• Spot urine sampling (15ml + 5x2ml will be stored at -80^oC in OPEN Biobank)
• Short Form 36 version 2 Health Questionnaire

Collaborating researchers and departments

Department of Urology, Odense University Hospital

• Sune Møller Jeppesen, BSc.med.

Urological Research Centre, Department of Urology, Odense University Hospital and University of Southern Denmark

• Professor Lars Lund, MD, DMSci, FCS (HK)

Department of Endocrinology, Odense University Hospital

• Knud Bonnet Yderstræde, MD, PhD

Department of Nephrology, Odense University Hospital

• Claus Bistrup, MD, PhD

Institute of Molecular Medicine, University of Southern Denmark

• Professor Boye L. Jensen, MD, PhD, DMSci

Department of Urology, Charing Cross Hospital

• Imperial College Healthcare NHS Trust, London, UK , Milad Hanna, MD