Short summary

A randomized placebo-controlled multicentre trial testing the effect of the mineralocorticoid antagonist spironolactone on renal function and fibrosis in kidney transplant patients

Rationale

Calcineurin inhibitors (CNI) are one of the cornerstones of the immunosuppressive therapy after solid organ transplantation. The introduction of CNI has caused a significant decrease in acute rejections. However, CNI also have severe side effects including renal interstitial fibrosis and tubular atrophy - also referred to as CNI nephrotoxicity. In the transplanted kidney this contributes to impaired kidney function and eventually reduced graft survival.

The mineralocorticoid hormone aldosterone may be involved in the development of renal fibrosis. Recent observations suggest that aldosterone plays a central role in the pathogenesis of CNI nephrotoxicity and that the mineralocorticoid-receptor-blocker spironolactone could be a useful agent to prevent it.

The SPIREN trial tests whether spironolactone as an add-on to standard therapy in 188 kidney transplant patients for three years preserves renal function and reduces the formation of fibrosis in the transplanted kidney.

Description of the cohort

188 kidney transplant patients from four centres: Odense, Kolding, Skejby and Rigshospitalet.

Inclusion criteria

1. Age > 18 years

2. Proteinuria < 3 g/day

3. Creatinine clearance ≥ 30 mL/min

4. Plasma potassium < 5.5 mmol/L

5. Negative pregnancy test at inclusion for women of childbearing potential and adequate contraception throughout the trial

Exclusion criteria

1. Former intolerance of spironolactone

2. Resonium or Digoxin treatment

3. Pregnancy or planned pregnancy

4. Clinically relevant organic, systemic or psychological disorder

5. Expectation of non-compliance

Data and biological material

Subjects are randomized to spironolactone or placebo for three years. At visits every three months data regarding adverse events, blood pressure and safety blood samples. At yearly visits we perform ChromEDTA clearance, 24-hour urine sample, ambulatory blood pressure and in a subgroup a renal biopsy at baseline and after two years of participation.

Biobank samples include plasma and urine collected yearly for the three years of intervention.

Collaborating researchers and departments

Department of Nephrology, Odense University Hospital

• MD, PhD Claus Bistrup
• MD, PhD Helle C. Thiesson

Department of Nephrology, Skejby Hospital

• Professor Bente Jespersen

Clinic for Nephrology, Rigshospitalet

• Dr.med. Martin Egfjord

Department of Kidney Diseases, Hospital of Lillebaelt, Kolding

• MD Birgitte Tougaard
• MD, PhD Donata Cibulskyte

Department of Pathology, Odense University Hospital

• Professor Niels Marcussen

Institute for Molecular Medicine, University of Southern Denmark

• Professor Boye L. Jensen