Ignite Creation Date:
2024-10-26 @ 3:38 PM
Last Modification Date:
2024-10-26 @ 3:38 PM
Study NCT ID:
NCT06560801
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-08-12
Brief Title:
Dapagliflozin on Renal Morphology and Renal Perfusion in Patients One Year After Kidney Transplantation
Sponsor:
None
Organization:
None
Study Overview
Official Title:
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
Status:
RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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 11 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
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 11 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
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 ACEiARBs 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 Previouslythe 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 Fouriers 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 ie 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
For the last years renin-angiotensin-aldosterone blockade agents ACEiARBs 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 Previouslythe 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 Fouriers 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 ie 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None