Dapagliflozin on Renal Morphology and Renal Perfusion in Patients One Year After Kidney Transplantation

Randomized Clinical Study to Analyse the Effects of Dapagliflozin on Renal Morphology and Renal Perfusion in Patients With Impaired Renal Function One Year After Kidney Transplantation

The aim of this study is to observe the mechanisms of dapagliflozin on the renal interstitial tissue and renal perfusion. For this purpose, renal transplanted patients as an excellent model of CKD and high cardiovascular risk (similar to patients in DAPA-CKD study) are included in this study.

The objectives of the study are to analyze the effects of dapagliflozin on renal morphology and renal perfusion in patients with impaired renal function one year after kidney transplantation. This is a randomized (1:1), single centre clinical study. Each patient will be randomly assigned in an unblinded fashion to 10 mg Dapagliflozin or not 9 months after transplantation. At least 48 patients will be randomized and included. The routine renal biopsy taken one year after kidney transplantation will allow us to determine the morphological integrity of peritubular fibroblasts, interstitial inflammatory cell density and investigate markers of inflammation, oxidative stress and nitic oxide synthase expression (iNOS).

Study Overview

• Status: Recruiting
• Conditions: Chronic Kidney Diseases
• Intervention / Treatment: Drug: Dapagliflozin 10mg Tab

Detailed Description

Chronic kidney disease (CKD) has a high prevalence globally and is a global health concern. CKD is associated with increased risks of cardiovascular morbidity, mortality and decreased quality of life in all stages of the disease. Most patients with CKD die of cardiovascular events in earlier stages before end-stage renal disease develops.

For the last years, renin-angiotensin-aldosterone blockade agents (ACEi/ARBs) were the only treatment available for managing CKD in both native and kidney transplant patients. Recently, sodium-glucose transport protein 2 inhibitors (SGLT2i) emerged as a new class of therapeutics for diabetic CKD, non-diabetic proteinuric CKD, and heart failure with and without type 2 diabetes mellitus (T2DM) in patients with native kidneys.

Dapagliflozin (SGLT2i) has been shown to be cardio- and nephroprotective in patients with and without T2DM. The DAPA-CKD trial found that patients with CKD treated with dapagliflozin had a lower risk of the primary composite outcome of a sustained decline in the estimated glomerular filtration rate (eGFR) of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes than patients who were assigned to receive placebo. Similar results have been confirmed by other SGLT2i in 2022 (Empagliflozin; EMPA-KIDNEY trial). In April 2021, Dapagliflozin became the first SGLT2i to be approved by the Food and Drug Administration (FDA) for the treatment of chronic kidney disease (CKD) regardless of diabetic status.

The anti-hyperglycaemic and anti-hypertensive effects of Dapagliflozin have been extensively studied and demonstrated in a number of clinical trials as well as in a real-world care setting. Previously,the investigators have demonstrated treatment with dapagliflozin in patients with T2DM improved diabetic control and reduced blood pressure (BP) in comparison to placebo. Furthermore, the drug was capable of reducing hyperperfusion of retinal capillaries and minimizing arteriole remodelling, factors that contribute to the progression of diabetic retinopathy, known to be linked with diabetic nephropathy. However, the precise mechanisms of its nephroprotective potential are still under discussion and needs to be elucidated.

Recently, the investigators described the intrarenal and glomerular hemodynamics of SGLT2i assessed by the clearance technique. SGLT2-inhibition impacts predominantly on post glomerular site, decreases renal vascular resistance and preserves renal perfusion in patients with type 2 diabetes and, thereby preserve renal function.

Vascular, glomerular and tubular effects of SGLT2i are discussed based on experimental and rarely on human data. Since the SGLT2 transporter has a high oxygen demand, relative hypoxia occurs in the renal interstitial tissue, with morphological changes of the fibroblasts (impairing erythropoietin production). In addition, the high glucose milieu in the interstitium also causes increased oxidative stress and triggers inflammatory responses that may cause increased glomerular permeability (despite upregulation of nitric oxide synthesis) and interstitial fibrosis. The aim of this study is to observe the mechanisms of dapagliflozin on the renal interstitial tissue (histology, urinary and serum markers indicative of histological integrity) and renal perfusion. For this purpose, renal transplanted patients as an excellent model of CKD and high cardiovascular risk (similar to patients in DAPA-CKD study) are included in this study. In addition, the investigators obtain clinical data of SGLT2i administered in patients after kidney transplantation.

Up to date the use SGLT2i appear to be safe in patients after renal transplantation based on data from pilot studies. However, renal transplanted patients were not included in the large preapproval randomized placebo-controlled trials. So, treatment with SGLT2i in renal transplanted patients with CKD is not obligatory. Recently, a review has been published summarizing the potential benefits and concerns of these agents in the context of kidney transplantation. In summary, the frequency of reported adverse effects in kidney transplant recipients does not appear to exceed those found in non-transplant patients or in kidney transplant recipients in the absence of SGLT2i therapy. In particular, the incidence of urinary tract infections with SGLT2i were consistent with previously reported incidence rates of the same and there were no reported incidences of Fourier's gangrene.

Along with the histological parameters, the investigators assess parameters of the renal circulation including total renal perfusion, separate cortical and medullary renal perfusion and renal vascular resistance in this cohort using arterial spin labeling magnetic resonance imaging (ASL-MRI). Of note, we have demonstrated that renal perfusion assessed by ASL-MRI is valid, plausible and reliable.

Several prospective studies reported a closer relation of organ damage with central (aortic) as opposed to peripheral (brachial) systolic blood pressure (BP), and central systolic BP was found to be independently associated with cardiovascular morbidity and mortality. In accordance, central pulse pressure has been repeatedly found to independently predict cardiovascular morbidity and mortality in various study cohorts. Further-more, prospective data have now been published showing that the forward and backward (reflected) wave amplitude predict independently cardiovascular complications. New advanced technology allows us to assess different vascular parameters. Previously, the investigators could demonstrate that the SGLT2i empagliflozin and dapagliflozin improved parameters of vascular function and arterial stiffness and decreased central (aortic) pulse and systolic pressures (i.e. afterload of the left ventricle) in patients with T2DM. Our results provided evidence for the concept that the better cardiovascular and renal outcomes observed with dapagliflozin and empagliflozin in the outcome studies are related to improved vascular function. In this study, these parameters are assessed to find out if the above mentioned results can be confirmed in patients after renal transplantation.

Our hypothesis is that dapagliflozin exerts beneficial effects on renal morphology, intrarenal inflammation and oxidative stress in patients with CKD. Moreover, improve vascular parameters and renal perfusion. Our approach would add valuable information for our pathophysiological understanding of the nephroprotective mechanisms of dapagliflozin in patients with CKD. In addition, the investigators obtain clinical data with respect to safety and effectiveness of SGLT2i administered in patients after kidney transplantation.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Bavaria
    • Erlangen, Bavaria, Germany, 91054
      • Recruiting
      • Clinical Research Center (CRC)
      • Contact: Dennis Kannenkeril, MD; Phone Number: 39002 +49913185; Email: dennis.kannenkeril@uk-erlangen.de
      • Contact: Roland E. Schmieder, MD; Phone Number: 39002 +499131 85

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Female and male patients aged between 18 and 75 years
• Patients with renal transplant having a stable eGFR, who are in stable condition, 9 months after transplantation, irrespective of their diabetes status
• Females of child bearing potential must be using adequate contraceptive precautions
• Females of childbearing potential or within two years of the menopause must have a negative urine pregnancy test at screening visit
• Informed consent (§ 40 Abs. 1 Satz 3 Punkt 3 AMG) has to be given in written form

Exclusion Criteria:

• Type 1 diabetes mellitus.
• HbA1c > 10%
• Use of SGLT-2 inhibitor within the past 2 months
• Any history of stroke, transient ischemic attack, instable angina pectoris, or myocardial infarction within the last 3 months prior to study inclusion.
• eGFR <25 ml/min/1.73m² (CKD-EPI Formula).
• Uncontrolled arterial hypertension (RR > 180/110 mmHg).
• Congestive heart failure (CHF) NYHA stage IV.
• Recurrent urinary tract infections (bacterial or fungal)
• Severe disorders of the gastrointestinal tract or other diseases which interfere the pharmacodynamics and pharmacokinetics of the drug.
• Significant laboratory abnormalities such as SGOT or SGPT levels more than 5 x above the upper limit of normal range.
• Antihypertensives are allowed but should be kept stable throughout the study period.
• Statins and other antihyperlipidemic drugs are allowed but should be kept stable throughout the study period.
• Drug or alcohol abusus
• Pregnant or breast-feeding patients
• Patients with contraindications to MRI

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dapagliflozin; Dapagliflozin + standard of care	Drug: Dapagliflozin 10mg Tab; Randomization will take place at visit 1 to either the group receiving standard care and dapagliflozin or standard care only.
No Intervention: Standard of care; standard of care only

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
renal morphology - fibroblasts	integrity of peritubular fibroblasts (PDGFRα) assessed from the routine one year follow up biopsy of the renal transplant	3 months after randomization
renal morphology - inflammation	markers of inflammation (example CD3, CD68, CD163) in the interstitium from the routine one year follow up biopsy of the renal transplant	3 months after randomization
renal morphology - oxidative stress	markers of oxidative stress (Nox1, 8-OHdG) in the interstitium assessed from the routine one year follow up biopsy of the renal transplant	3 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mRNA Expression profile of transcripts	mRNA Expression profile of transcripts relevant in renal transplantation using the Human Organ Transplant Panel of NanoString including 770 genes.	3 months after randomization
renal perfusion	renal perfusion of the renal transplant measured by ASL-MRI	3 months after randomization
central (aortic) systolic pressurepulse pressure	central (aortic) systolic pressure and pulse pressure	3 months after randomization
pulse pressure	pulse pressure	3 months after randomization

Collaborators and Investigators

• Sponsor: University of Erlangen-Nürnberg Medical School

Study record dates

Study Major Dates

• Study Start (Actual): July 28, 2023
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: August 12, 2024
• First Submitted That Met QC Criteria: August 15, 2024
• First Posted (Actual): August 19, 2024

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Renal Insufficiency; Pathological Conditions, Signs and Symptoms; Renal Insufficiency, Chronic; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; dapagliflozin
• Other Study ID Numbers: Dapa-TxV1.0

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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