The Effects of Spironolactone on Calcineurin Inhibitor Induced Nephrotoxicity (SPIREN)

The purpose of this study is to assess whether the diuretic drug spironolactone can prevent chronic damage to transplanted kidneys caused by the medication that prevents rejection.

Spironolactone prevents the effects of the hormone aldosterone. Aldosterone is suspected of being involved in the processes leading to chronic rejection of transplanted kidneys. Hence, by blocking the effects of aldosterone we hope to be able to prevent loss of kidney function in transplant patients.

Study Overview

• Status: Completed
• Conditions: Disorder Related to Renal Transplantation
• Intervention / Treatment: Drug: placebo; Drug: Spironolactone

Detailed Description

AIM: The purpose of this study is to assess whether spironolactone can prevent the formation of fibrosis in transplanted kidneys.

BACKGROUND: Calcineurin inhibitors (CNI) are one of the cornerstones of immunosuppressive therapy after kidney transplantation. The introduction of CNI has caused a significant decrease in acute rejections. However, CNI also have known side effects. These include the formation of tubulointerstitial fibrosis in the transplanted kidney, contributing over time to impaired kidney function and reduced graft survival.

The mineralocorticoid 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.

METHODS: This study is a randomized, placebo-controlled, double-blind study in which 170 renal transplant patients will be recruited from two nephrological departments in Southern Denmark. Patients will be randomized to three years of treatment with either spironolactone or placebo added to the standard immunosuppressive treatment. Renal graft biopsies, various molecular tests of tissue, blood and urine, chrome-EDTA clearance, 24-hour bloodpressure measurement and blood samples will be performed at inclusion, after 1 year, 2 years and upon completion.

• Study Type: Interventional
• Enrollment (Actual): 188
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Odense C, Denmark, 5000
    • Odense University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age > 18 years
2. Proteinuria < 3 g/24 hours
3. Creatinine clearance ≥ 30 mL/min
4. S-Potassium < 5,5 mmol/L
5. Negative pregnancy test at the inclusion and anticonception

Exclusion Criteria:

1. Intolerance to spironolactone
2. Creatinine clearance < 30 ml/min
3. S-Potassium ≥ 5,5 mmol/L
4. Resin or digoxine treatment
5. Pregnancy or planned pregnancy
6. Relevant organic, systemic or mental illness
7. Anticipation of lack of compliance or understanding the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: placebo
Experimental: Spironolactone	Drug: Spironolactone; One tablet per day (25 mg Spironolactone/placebo) for the first three months. Subsequently dosage is increased to two tablets per day (50 mg Spironolactone/placebo) for the rest of the study. In case of hyperkaliemia (>5,5 mmol/L) or intolerable side effects dosage will be reduced to one tablet per day (25 mg Spironolactone/placebo).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in Cr EDTA clearance	0, 1 year, 2 years, 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduced urine protein levels (change from baseline)		0, 1 year, 2 years, 3 years
Reduced fibrosis (change from baseline)	Verified by graft biopsies and immuno histochemistry. Newly transplanted patients will be subjected to additional biopsies 3 months and 1 year after inclusion.	0, 2 years
Reduced blood pressure (change from baseline)		0, 1 year, 2 years, 3 years
Cardiovascular events		3 years

Collaborators and Investigators

• Sponsor: Odense University Hospital
• Collaborators: Fredericia Hosptial
• Investigators: Study Director: Claus Bistrup, MD, ph.d., Dep. of Nephrology, Odense University Hospital

Publications and helpful links

General Publications

• Mortensen LA, Thiesson HC, Tougaard B, Egfjord M, Fischer ASL, Bistrup C. The effect of spironolactone on calcineurin inhibitor induced nephrotoxicity: a multicenter randomized, double-blind, clinical trial (the SPIREN trial). BMC Nephrol. 2018 May 3;19(1):105. doi: 10.1186/s12882-018-0885-6.

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (Actual): April 1, 2021
• Study Completion (Actual): April 1, 2021

Study Registration Dates

• First Submitted: May 17, 2012
• First Submitted That Met QC Criteria: May 18, 2012
• First Posted (Estimate): May 21, 2012

Study Record Updates

• Last Update Posted (Actual): September 9, 2021
• Last Update Submitted That Met QC Criteria: September 8, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Fibrosis; kidney transplant; chronic rejection; calcineurin inhibitor
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: Eudra CT: 2011-002243-98