MD, PhD-student
Mette Boye Boes
Research Unit of nephrology, University of Southern Denmark, and Department of Nephrology, Odense University Hospital
| Projekt styring | ||
| Projekt status | Open | |
| Data indsamlingsdatoer | ||
| Start | 01.09.2024 | |
| Slut | 31.12.2025 | |
Effect Camostat for Kidney Protection in Chronic Kidney Disease (CamKid)
Short summary
Chronic kidney disease (CKD) affects 10-15 % of the population. Proteinuria is a negative predictor of CKD progression and cardiovascular morbidity. We propose that aberrantly cofiltered serine proteases in the renal tubule causes progressive kidney injury through 1) complement activation and 2) proteolytic activation of ENaC. The present trial aims to evaluate the effect of Camostat Mesilate, a serine protease inhibitor, in patients with CKD and proteinuria and in healthy controls.
Rationale
Chronic kidney disease (CKD) is a progressive condition affecting approximately 10 % of the global population. Prevalence and mortality have remained stable through the last three decades, and CKD has now emerged as one of the leading causes of death globally. CKD is associated with various complications, such as hypertension, cardiovascular disease, metabolic bone disease, and premature death. As CKD progresses to end-stage kidney failure, expensive renal replacement therapies like dialysis or kidney transplantation are required. Proteinuria is an important prognostic factor for progression of CKD and is associated with increased cardiovascular morbidity and mortality. Reduction in proteinuria is associated with slower disease progression and improved cardiovascular outcomes. For decades the medical treatment options to slow down progression of CKD have been limited to inhibition of the renin-angiotensin system (RAASi), including ACE-inhibitors (ACEi) and angiotensin II receptor blockers (ARB). Although recent evidence on newer agents as sodium glucose transporter 2 inhibitors (SGLT2i), glucagon-like peptides-1 (GLP-1) agonists and nonsteroidal mineralocorticoid receptor antagonists have shown promising results in patients with CKD, there is still a need for understanding and targeting the underlying pathophysiology of CKD. The pathophysiological relation between proteinuria and progressive kidney injury is complex and still not fully understood. We propose a causal relation between proteinuria and progression of CKD through aberrant filtration of serine proteases most significantly plasmin but also kallikrein and prostasin. These proteases have in common the ability to proteolytically activate a) the epithelial sodium channel (ENaC) in the distal tubule and b) the co-filtered complement system precursors together causing sodium retention, expanded extracellular volume, and inflammation in the kidneys. We suggest that these independent, but serine protease driven mechanisms maintain a vicious cycle of progressive kidney injury and can be targeted pharmacologically by a serine protease inhibitor to attenuate the progression of CKD in patients with proteinuria. Camostat Mesilate (Foipan®, Ono Pharmaceuticals, Japan) is a well-known and well-tolerated serine protease inhibitor used for decades to treat chronic pancreatitis and postoperative reflux esophagitis in Japan. Preclinical data indicate that Camostat Mesilate suppresses the proteolytic activation of ENaC, reduces blood pressure, lowers proteinuria, and improves renal injury markers . We propose that Camostat Mesilate will mitigate CKD progression, hypertension, and cardiovascular disease in CKD patients with proteinuria. The overall aim of the project is to mitigate progression of CKD of any course and lower cardiovascular morbidity and mortality in CKD patients with proteinuria by repurposing a known drug. The specific objectives are to test whether CM, a serine protease inhibitor, may have previously undiscovered renoprotective effects by inhibiting serine protease activity and suppressing complement activation within the renal tubules. This trial is an interventional, non-randomized, open-label pharmacodynamic study to evaluate the effect of Camostat Mesilate in both CKD patients with proteinuria and healthy controls. This approach has been chosen as the trial serves as a pilot study, aiming to investigate a novel treatment target in CKD patients. Including healthy control allows a comparison of the effect of Camostat Mesilate on normal physiology versus CKD with proteinuria. Both patients and controls will follow a fixed sodium diet of 150 mmol/day for a duration of 8 days. On the fifth day of this diet, administration of oral CM 200 mg x3/day for four days while the diet is continued. CKD patients will receive CM as an add-on to their current treatment regimen. Blood samples, 24-hour urine samples, home blood pressure, and body composition monitor (BCM) measurement will be obtained at baseline, after 4 days on the diet just before treatment and after completion of 4 days treatment with Camostat Mesilate, after which the study is completed. The primary effect parameters are urine sodium and water excretion, body water content/weight and home blood pressure. Secondary endpoints are tubular complement activation, urine protease activity, ENaC activation, 24 hours urine albumin excretion and plasma concentrations of renin, angiotensin II, aldosterone and NT-proBNP.
Description of the cohort
The trial includes both patients with chronic kidney disease and proteinuria recruited from the Department of Nephrology at Odense University hospital and healthy controls recruited from local institutions and social media.
Data and biological material
Demographics, diagnosis, data from medical journal, blood samples, urine samples, anthropometric data (blood pressure, BCM, weight).
Collaborating researchers and departments
Cardiovascular and Renal Research, Institute of Molecular Medicine, SDU