Proteinuria in Renal Transplant Patients Treated With Dapagliflozin (DAPAGREFFE)

Evolution of Proteinuria in Renal Transplant Patients Treated With Dapagliflozin for Nephroprotection. DAPAGREFFE

The prevalence of chronic kidney disease is rising steadily and represents a major public health challenge. Hypertension and proteinuria are two factors strongly associated with the progression of chronic kidney disease (CKD) and the high risk of cardiovascular complications. Achieving blood pressure control and reducing proteinuria is therefore a major objective in the management of chronic renal failure. Until recently, inhibitors of the renin-angiotensin-aldosterone system were the only therapeutic class known to have both anti-proteinuric and anti-hypertensive action, reducing the risk of progression to end-stage renal disease.

The Investigators intend to conduct an observational study with the primary objective of studying the evolution of proteinuria in kidney transplant patients treated with dapagliflozin according to the marketing authorization. The secondary objectives of the study are to investigate other expected benefits, including effects on renal function and metabolic effects, as well as potential side-effects of this treatment in this population.

Study Overview

• Status: Recruiting
• Conditions: Chronic Kidney Diseases
• Intervention / Treatment: Procedure: Follow-up at D14; Procedure: Follow-up at M1

Detailed Description

Recent years have seen the emergence of sodium-glucose co-transporter type 2 (SGLT2) inhibitors, also known as gliflozins, which represent a real therapeutic innovation in the management of type 2 diabetes, heart failure and chronic kidney disease.

The prevalence of chronic kidney disease is rising steadily and represents a major public health challenge. Hypertension and proteinuria are two factors strongly associated with the progression of chronic kidney disease (CKD) and the high risk of cardiovascular complications. Achieving blood pressure control and reducing proteinuria is therefore a major objective in the management of chronic renal failure. Until recently, inhibitors of the renin-angiotensin-aldosterone system were the only therapeutic class known to have both anti-proteinuric and anti-hypertensive action, reducing the risk of progression to end-stage renal disease.

Several large international studies, initially investigating the efficacy of SGLT2 inhibitors as anti-diabetic therapy, reported that this new therapeutic class reduced the risk of cardiovascular complications and end-stage renal disease. This nephroprotective and cardioprotective effect was independent of the anti-diabetic effect of the drug. The nephroprotective effect is explained in particular by a decrease in proteinuria via a reduction in glomerular hyperfiltration, and a reduction in intraglomerular pressure via vasoconstriction of the afferent artery in response to the blockade of glucose and sodium reabsorption in the proximal convoluted tubule.

An international study (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease study) was specifically designed to investigate the nephroprotective effect of dapagliflozin in both diabetic and non-diabetic proteinuric CKD patients. This study, which included 4,300 patients with glomerular filtration rate (GFR) between 25 and 75ml/min/1.73m2 and an albuminuria/creatinuria ratio between 200 and 5,000mg/g, confirmed a significant reduction in proteinuria, a lower risk of progression to end-stage CKD and a lower mortality rate in patients treated with dapagliflozin compared with those who received placebo. Following this study, Dapagliflozin was granted marketing authorization in France in October 2021 for any patient with chronic kidney disease, in patients with a GFR between 25 and 75ml/min/1.73m2 and an albuminuria/creatinuria ratio between 200 and 5000mg/g despite treatment with converting enzyme inhibitor/Angiotensin II receptor antagonists for at least 4 weeks. Renal transplantation is not a contraindication to the use of dapagliflozin, so renal transplant patients meeting these same criteria may receive dapagliflozin as nephroprotective therapy. However, few data are currently available on the evolution of proteinuria and GFR in this population.

After renal transplantation, proteinuria is also a major factor associated with impaired graft function and cardiovascular risk. However, transplant patients have specific characteristics compared with non-transplant CKD patients: by definition, they have a single functional kidney and receive immunosuppressive treatments that modify renal hemodynamics, including calcineurin inhibitors, drugs that also have a vasoconstrictive effect. In addition, a moderate increase in the risk of urinary tract infection and genital mycotic infection has been reported with the use of gliflozins, necessitating careful monitoring of the incidence of these side effects in this population.

The investigators have been progressively introducing the use of dapagliflozin as a nephroprotective treatment in transplant patients meeting marketing authorisation criteria (chronic renal failure with GFR between 25-75ml/min/1.73m2, albuminuria/creatinuria ratio 200-5000mg/g despite treatment with converting enzyme inhibitors and Angiotensin II receptor antagonists for at least 4 weeks) within the nephrology department of Montpellier University Hospital for several months. To date, more than 30 transplant patients have been treated with dapagliflozin (of whom 12 treated patients have usable data and may be included retrospectively in this study). In this recent experience, a very good safety profile was observed and no drug interactions were identified. Although a reduction in early proteinuria was observed, the follow-up of these patients is not yet long enough to carry out a preliminary analysis.

The investigators intend to conduct an observational study with the primary objective of studying the evolution of proteinuria in kidney transplant patients treated with dapagliflozin according to marketing authorization criteria. The secondary objectives of the study are to investigate other expected benefits, including effects on renal function and metabolic effects, as well as potential side-effects of this treatment in this population.

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Vincent PERNIN, MD; Phone Number: 033 467.33.84.80; Email: v-pernin@chu-montpellier.fr

Study Locations

• France
  • Montpellier, France, 34295
    • Recruiting
    • University Hospital of Montpellier
    • Contact: Vincent PERNIN, MD; Phone Number: 033 467 33 84 80; Email: v-pernin@chu-montpellier.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Initiation of dapagliflozin less than 14 days ago for chronic kidney disease
• Glomerular Filtration Rate (GFR) (by CKD-EPI) between 25 and 75 ml.min.1.73m².
• Albuminuria/Creatinuria ratio between 200 mg/g and 5000 mg/g
• Treatment with an ACE inhibitor or angiotensin 2 receptor blocker (ARA II or sartan) at the maximum tolerated dose for at least 4 weeks.
• Age ≥ 18 years

Exclusion Criteria:

• For study group (CKD Renal transplant recipients) : Renal transplantation < 1 year old
• For the control group (non-transplanted CKD) : history of transplantation of an other organ than a kidney initiation or modification of immunosuppressive therapy less than 6 months ago (except temporary discontinuation for infection or change in dosage)
• Type 1 diabetes
• Severe liver failure (Child-Pugh stage C)
• Intolerance to any of the excipients of Forxiga®, in particular lactose intolerance
• Patient undergoing treatment with another SGLT2 inhibitor (sodium-glucose co-transporter type 2)
• Patient enrolled in another clinical trial
• Pregnancy or breast-feeding
• Guardianship or trusteeship
• Patient protected by law
• Subject not affiliated to a social security scheme, or not benefiting from such a scheme
• Patient deprived of liberty
• For the retrospective cohort: Patient's refusal to take part in the study after receiving the information note.
• For the prospective cohort: Failure to obtain written informed consent after a period of reflection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Dapagliflozine; For prospective cohort, an additional follow-up at D14 and M1 will be carried out.	Procedure: Follow-up at D14; A blood test and urinary test will be performed at D14.; Procedure: Follow-up at M1; A blood test and urinary test will be performed at M1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in albuminuria/creatinuria ratio at 6 months	decrease in albuminuria/creatinuria ratio ≥ 50% from baseline or achievement of albuminuria/creatinuria ratio ≤ 30 mg/g	From baseline to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in albuminuria/creatinuria ratio at 3 months	decrease in albuminuria/creatinuria ratio ≥ 50% from baseline or achievement of albuminuria/creatinuria ratio ≤ 30 mg/g	From baseline to 3 months
Change in glomerular filtration rate (GFR)	Decrease ≥ 50% in glomerular filtration rate (GFR) from baseline to M3 and M6	From baseline to 3 and 6 months
Number of patients with end-stage chronic kidney disease (CKD)	Number of patients with end-stage CKD as defined by dialysis or pre-emptive transplant replacement therapy	From baseline to 3 and 6 months
Number of episodes of acute renal failure	Numbers of episodes of acute renal failure defined according to KDIGO criteria (stage I: increase in serum creatinine ≥ 26.52 micromoles/L in 48 hours or increase in serum creatinine of ≥ 1.5 times the initial value in the preceding 7 days, stage II: increase in serum creatinine ≥ 2 times the initial value, stage III: increase in serum creatinine ≥ 3 times the initial value or serum creatinine ≥ 353. 6 mmol/l or need to start extrarenal purification	From baseline to 3 and 6 months
Death rate	Death rate from any cause	From baseline to 3 and 6 months
Study of interaction with immunosuppressive treatments	Study of interaction with immunosuppressive treatments (residual rate and change in dosage of immunosuppressive treatment)	From baseline to 3 and 6 months
Changes in blood pressure	Systolic blood pressure and diastolic blood pressure are measured in Mmhg	From baseline to 3 and 6 months
Changes in weight	Weight is measured in kg.	From baseline to 3 and 6 months
Changes in Hba1c	The dosage of glycated hemoglobin is expressed as a percentage.	From baseline to 3 and 6 months
Occurrence of infectious side effects	Occurrence of infectious side effects, including urinary tract infections, genital mycotic infections, Fournier's gangrene at M3 and M6	From baseline to 3 and 6 months
Occurrence of metabolic side effects	Occurrence of metabolic side effects including diabetic ketoacidosis, hypoglycemia, dehydration, hypotension, hydrosodium depletion at M3 and M6	From baseline to 3 and 6 months
Other adverse reactions associated with dapagliflozin at M3 and M6	Other adverse reactions : non-infectious and non-metabolic associated with dapagliflozin at M3 and M6	From baseline to 3 and 6 months
Discontinuation of treatment for side effects	Discontinuation of treatment for side effects	From baseline to 3 and 6 months

Collaborators and Investigators

• Sponsor: University Hospital, Montpellier

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2024
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: November 20, 2023
• First Submitted That Met QC Criteria: December 8, 2023
• First Posted (Actual): December 11, 2023

Study Record Updates

• Last Update Posted (Actual): January 12, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Urological Manifestations; Disease Attributes; Renal Insufficiency; Urination Disorders; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Renal Insufficiency, Chronic; Proteinuria
• Other Study ID Numbers: RECHMPL23_0102; 2023-506295-26-00 (Other Identifier: EMA)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No